128 results on '"Mitochondrial complexes"'
Search Results
2. Azo food dye neurotoxicity in rats: A neurobehavioral, biochemical, and histopathological study
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Biswas, Pronit, Jain, Juli, Hasan, Whidul, Bose, Devasish, and Yadav, Rajesh Singh
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- 2023
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Catalog
3. Off‐target effects of statins: molecular mechanisms, side effects and the emerging role of kinases.
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Lagunas‐Rangel, Francisco Alejandro, Liepinsh, Edgars, Fredriksson, Robert, Alsehli, Ahmed M., Williams, Michael J., Dambrova, Maija, Jönsson, Jörgen, and Schiöth, Helgi B.
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EPIDERMAL growth factor receptors , *PROTEIN-tyrosine kinases , *KINASES , *STATINS (Cardiovascular agents) , *MITOCHONDRIA - Abstract
Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on‐ (targeting 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase [HMGCR]) and off‐target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb‐b2 receptor tyrosine kinase 2 (HER2) and MET proto‐oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto‐oncogene, non‐receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator‐activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off‐target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off‐target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer. [ABSTRACT FROM AUTHOR] more...
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- 2024
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4. Skeletal muscle hypertrophy and enhanced mitochondrial bioenergetics following electrical stimulation exercises in spinal cord injury: a randomized clinical trial
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Gorgey, Ashraf S., Khalil, Refka E., Carter, William, Rivers, Jeannie, Chen, Qun, and Lesnefsky, Edward J.
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- 2024
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5. High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage.
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Berdún, Rebeca, Obis, Èlia, Mota-Martorell, Natàlia, Bassols, Anna, Valent, Daniel, Serrano, José C. E., Martín-Garí, Meritxell, Rodríguez-Palmero, María, Moreno-Muñoz, José Antonio, Tibau, Joan, Quintanilla, Raquel, Pamplona, Reinald, Portero-Otín, Manuel, and Jové, Mariona more...
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UNSATURATED fatty acids ,FAT ,MITOCHONDRIA ,MITOCHONDRIAL proteins ,HIGH-fat diet ,OBESITY - Abstract
Obesity is a risk factor for highly prevalent age-related neurodegenerative diseases, the pathogenesis of whichinvolves mitochondrial dysfunction and protein oxidative damage. Lipoxidation, driven by high levels of peroxidizable unsaturated fatty acids and low antioxidant protection of the brain, stands out as a significant risk factor. To gain information on the relationship between obesity and brain molecular damage, in a porcine model of obesity we evaluated (1) the level of mitochondrial respiratory chain complexes, as the main source of free radical generation, by Western blot; (2) the fatty acid profile by gas chromatography; and (3) the oxidative modification of proteins by mass spectrometry. The results demonstrate a selectively higher amount of the lipoxidation-derived biomarker malondialdehyde-lysine (MDAL) (34% increase) in the frontal cortex, and positive correlations between MDAL and LDL levels and body weight. No changes were observed in brain fatty acid profile by the high-fat diet, and the increased lipid peroxidative modification was associated with increased levels of mitochondrial complex I (NDUFS3 and NDUFA9 subunits) and complex II (flavoprotein). Interestingly, introducing n3 fatty acids and a probiotic in the high-fat diet prevented the observed changes, suggesting that dietary components can modulate protein oxidative modification at the cerebral level and opening new possibilities in neurodegenerative diseases' prevention. [ABSTRACT FROM AUTHOR] more...
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- 2024
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- View/download PDF
6. The constraints of allotopic expression.
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Nieto-Panqueva, Felipe, Rubalcava-Gracia, Diana, Hamel, Patrice P., and González-Halphen, Diego
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GENE expression , *MEMBRANE proteins , *TRANSLOCATOR proteins , *COLOR codes , *ENDOCYTOSIS , *MITOCHONDRIAL membranes - Abstract
• We describe the natural transfer of mitochondrial OXPHOS genes to the nucleus and critically review claims of their allotopic expression. • We discuss three constraints that should be considered when modifying a mitochondrial gene for allotopic expression. • The TIM23 translocator sorts alpha-helices through two different routes that eventually determine the final topology of membrane proteins. • We assigned a color code to the transmembrane stretches (TMS) of OXPHOS proteins to predict which are likely to be internalized into mitochondria. • We propose that the design of proteins for allotopic expression must make allowance for μΔG app maximization of highly hydrophobic TMS. Allotopic expression is the functional transfer of an organellar gene to the nucleus, followed by synthesis of the gene product in the cytosol and import into the appropriate organellar sub compartment. Here, we focus on mitochondrial genes encoding OXPHOS subunits that were naturally transferred to the nucleus, and critically review experimental evidence that claim their allotopic expression. We emphasize aspects that may have been overlooked before, i.e., when modifying a mitochondrial gene for allotopic expression━besides adapting the codon usage and including sequences encoding mitochondrial targeting signals━three additional constraints should be considered: (i) the average apparent free energy of membrane insertion (μΔG app) of the transmembrane stretches (TMS) in proteins earmarked for the inner mitochondrial membrane, (ii) the final, functional topology attained by each membrane-bound OXPHOS subunit; and (iii) the defined mechanism by which the protein translocator TIM23 sorts cytosol-synthesized precursors. The mechanistic constraints imposed by TIM23 dictate the operation of two pathways through which alpha-helices in TMS are sorted, that eventually determine the final topology of membrane proteins. We used the biological hydrophobicity scale to assign an average apparent free energy of membrane insertion (μΔG app) and a "traffic light" color code to all TMS of OXPHOS membrane proteins, thereby predicting which are more likely to be internalized into mitochondria if allotopically produced. We propose that the design of proteins for allotopic expression must make allowance for μΔG app maximization of highly hydrophobic TMS in polypeptides whose corresponding genes have not been transferred to the nucleus in some organisms. [ABSTRACT FROM AUTHOR] more...
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- 2023
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7. Identification of mitochondrial respiratory chain signature for predicting prognosis and immunotherapy response in stomach adenocarcinoma
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Jing Yang, Feifan Jin, Huanjuan Li, Yuhuan Shen, Weilin Shi, Lina Wang, Lei Zhong, Gongqiang Wu, Qiaoliang Wu, and Yanchun Li
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Stomach adenocarcinoma ,Mitochondrial complexes ,Tumor microenvironment ,Microsatellite instability ,Prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Stomach adenocarcinoma (STAD) is the third leading cause of cancer-related deaths and the fifth most prevalent malignancy worldwide. Mitochondrial respiratory chain complexes play a crucial role in STAD pathogenesis. However, how mitochondrial respiratory chain complex genes (MRCCGs) affect the prognosis and tumor microenvironment in STAD remains unclear. In this study, we systematically analyzed genetic alterations and copy number variations of different expression densities of MRCCGs, based on 806 samples from two independent STAD cohorts. Then we employed the unsupervised clustering method to classify the samples into three expression patterns based on the prognostic MRCCG expressions, and found that they were involved in different biological pathways and correlated with the clinicopathological characteristics, immune cell infiltration, and prognosis of STAD. Subsequently, we conducted a univariate Cox regression analysis to identify the prognostic value of 1175 subtype-related differentially expressed genes (DEGs) and screened out 555 prognostic-related genes. Principal component analysis was performed and developed the MG score system to quantify MRCCG patterns of STAD. The prognostic significance of MG Score was validated in three cohorts. The low MG score group, characterized by increased microsatellite instability-high (MSI-H), tumor mutation burden (TMB), PD-L1 expression, had a better prognosis. Interestingly, we demonstrated MRCCG patterns score could predict the sensitivity to ferroptosis inducing therapy. Our comprehensive analysis of MRCCGs in STAD demonstrated their potential roles in the tumor-immune-stromal microenvironment, clinicopathological features, and prognosis. Our findings highlight that MRCCGs may provide a new understanding of immunotherapy strategies for gastric cancer and provide a new perspective on the development of personalized immune therapeutic strategies for patients with STAD. more...
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- 2023
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8. Identification of mitochondrial respiratory chain signature for predicting prognosis and immunotherapy response in stomach adenocarcinoma.
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Yang, Jing, Jin, Feifan, Li, Huanjuan, Shen, Yuhuan, Shi, Weilin, Wang, Lina, Zhong, Lei, Wu, Gongqiang, Wu, Qiaoliang, and Li, Yanchun
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GENE expression ,MITOCHONDRIA ,STOMACH ,PROGNOSIS ,PRINCIPAL components analysis - Abstract
Stomach adenocarcinoma (STAD) is the third leading cause of cancer-related deaths and the fifth most prevalent malignancy worldwide. Mitochondrial respiratory chain complexes play a crucial role in STAD pathogenesis. However, how mitochondrial respiratory chain complex genes (MRCCGs) affect the prognosis and tumor microenvironment in STAD remains unclear. In this study, we systematically analyzed genetic alterations and copy number variations of different expression densities of MRCCGs, based on 806 samples from two independent STAD cohorts. Then we employed the unsupervised clustering method to classify the samples into three expression patterns based on the prognostic MRCCG expressions, and found that they were involved in different biological pathways and correlated with the clinicopathological characteristics, immune cell infiltration, and prognosis of STAD. Subsequently, we conducted a univariate Cox regression analysis to identify the prognostic value of 1175 subtype-related differentially expressed genes (DEGs) and screened out 555 prognostic-related genes. Principal component analysis was performed and developed the MG score system to quantify MRCCG patterns of STAD. The prognostic significance of MG Score was validated in three cohorts. The low MG score group, characterized by increased microsatellite instability-high (MSI-H), tumor mutation burden (TMB), PD-L1 expression, had a better prognosis. Interestingly, we demonstrated MRCCG patterns score could predict the sensitivity to ferroptosis inducing therapy. Our comprehensive analysis of MRCCGs in STAD demonstrated their potential roles in the tumor-immune-stromal microenvironment, clinicopathological features, and prognosis. Our findings highlight that MRCCGs may provide a new understanding of immunotherapy strategies for gastric cancer and provide a new perspective on the development of personalized immune therapeutic strategies for patients with STAD. [ABSTRACT FROM AUTHOR] more...
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- 2023
- Full Text
- View/download PDF
9. High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage
- Author
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Rebeca Berdún, Èlia Obis, Natàlia Mota-Martorell, Anna Bassols, Daniel Valent, José C. E. Serrano, Meritxell Martín-Garí, María Rodríguez-Palmero, José Antonio Moreno-Muñoz, Joan Tibau, Raquel Quintanilla, Reinald Pamplona, Manuel Portero-Otín, and Mariona Jové more...
- Subjects
obesity ,lipoxidation ,mitochondrial complexes ,n3 PUFA ,probiotics ,age-related neurodegenerative diseases ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Obesity is a risk factor for highly prevalent age-related neurodegenerative diseases, the pathogenesis of whichinvolves mitochondrial dysfunction and protein oxidative damage. Lipoxidation, driven by high levels of peroxidizable unsaturated fatty acids and low antioxidant protection of the brain, stands out as a significant risk factor. To gain information on the relationship between obesity and brain molecular damage, in a porcine model of obesity we evaluated (1) the level of mitochondrial respiratory chain complexes, as the main source of free radical generation, by Western blot; (2) the fatty acid profile by gas chromatography; and (3) the oxidative modification of proteins by mass spectrometry. The results demonstrate a selectively higher amount of the lipoxidation-derived biomarker malondialdehyde-lysine (MDAL) (34% increase) in the frontal cortex, and positive correlations between MDAL and LDL levels and body weight. No changes were observed in brain fatty acid profile by the high-fat diet, and the increased lipid peroxidative modification was associated with increased levels of mitochondrial complex I (NDUFS3 and NDUFA9 subunits) and complex II (flavoprotein). Interestingly, introducing n3 fatty acids and a probiotic in the high-fat diet prevented the observed changes, suggesting that dietary components can modulate protein oxidative modification at the cerebral level and opening new possibilities in neurodegenerative diseases’ prevention. more...
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- 2024
- Full Text
- View/download PDF
10. Modulation of mitochondrial functions contributes to the protection of lamotrigine against Alzheimer's disease.
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Fu XX, Wei B, Huang ZH, Duan R, Deng Y, E Y, Wang SY, Chen SY, Zhang YD, and Jiang T
- Abstract
Background: Our previous studies have established that the broad-spectrum anti-epileptic drug lamotrigine (LTG) confers protection against cognitive impairments, synapse and nerve cell damage, as well as characteristic neuropathologies in APP/PS1 mice, a mouse model of Alzheimer's disease (AD). However, the precise molecular mechanisms responsible for this protective effect induced by LTG remain largely elusive., Objective: In this study, we aimed to investigate the mechanisms underlying the beneficial effects of LTG against AD., Methods: Five-month-old APP/PS1 mice were treated with 30 mg/kg of LTG daily for three consecutive months. Subsequently, high-throughput ribosome profiling sequencing was conducted to identify differentially translated genes (DTGs) rescued by LTG in the brains of these mice. To gain further insights into the potential functions and pathways of these LTG-rescued DTGs, gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. RNA expression, protein levels, and translational efficiency were assessed to explore how LTG regulated gene expression processes in AD-related DTGs. Additionally, Aβ
42 peptide-stimulated primary neurons were used to uncover the potential mechanisms and signaling pathway by which LTG mitigated oxidative stress under AD context., Results: For the first time, we reveal that LTG inactivates mitochondrial complexes in the brains of APP/PS1 mice by suppressing the translational efficiency of mitochondrial complexes-related genes. More importantly, we demonstrate that LTG mitigates mitochondrial-mediated oxidative stress in neurons within the context of AD by activation of SIRT6/PGC-1α pathway., Conclusions: These findings provide further insights into the mechanisms underlying the protective effects of LTG against AD., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. more...- Published
- 2025
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11. Regional heterogeneity in mitochondrial function underlies region specific vulnerability in human brain ageing: Implications for neurodegeneration.
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Anusha-Kiran, Yarlagadda, Mol, Praseeda, Dey, Gourav, Bhat, Firdous Ahmad, Chatterjee, Oishi, Deolankar, Sayali Chandrashekhar, Philip, Mariamma, Prasad, T.S. Keshava, Srinivas Bharath, M.M., and Mahadevan, Anita more...
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MICROTUBULE-associated proteins , *TUBULINS , *MITOCHONDRIA , *TAU proteins , *MEDULLA oblongata - Abstract
Selective neuronal vulnerability (SNV) of specific neuroanatomical regions such as frontal cortex (FC) and hippocampus (HC) is characteristic of age-associated neurodegenerative diseases (NDDs), although its pathogenetic basis remains unresolved. We hypothesized that physiological differences in mitochondrial function in neuroanatomical regions could contribute to SNV. To investigate this, we evaluated mitochondrial function in human brains (age range:1–90 y) in FC, striatum (ST), HC, cerebellum (CB) and medulla oblongata (MD), using enzyme assays and quantitative proteomics. Striking differences were noted in resistant regions- MD and CB compared to the vulnerable regions- FC, HC and ST. At younger age (25 ± 5 y), higher activity of electron transport chain enzymes and upregulation of metabolic and antioxidant proteins were noted in MD compared to FC and HC, that was sustained with increasing age (≥65 y). In contrast, the expression of synaptic proteins was higher in FC, HC and ST (vs. MD). In line with this, quantitative phospho-proteomics revealed activation of upstream regulators (ERS, PPARα) of mitochondrial metabolism and inhibition of synaptic pathways in MD. Microtubule Associated Protein Tau (MAPT) showed overexpression in FC, HC and ST both in young and older age (vs. MD). MAPT hyperphosphorylation and the activation of its kinases were noted in FC and HC with age. Our study demonstrates that regional heterogeneity in mitochondrial and other cellular functions contribute to SNV and protect regions such as MD, while rendering FC and HC vulnerable to NDDs. The findings also support the "last in, first out" hypothesis of ageing, wherein regions such as FC , that are the most recent to develop phylogenetically and ontogenetically, are the first to be affected in ageing and NDDs. [Display omitted] • The processes contributing to region-specific selective neuronal vulnerability (SNV) and their accrual during aging is underexplored in human brains. • We noted that regional mitochondrial, antioxidant and synaptic heterogeneity based on expression and phosphorylation dynamics underlies the SNV of frontal cortex (FC) and hippocampus (HC) to neurodegeneration. • Expression and phosphorylation profile of microtubule associated protein tau (MAPT) and associated kinases during ageing in FC and HC, also probably contributes to SNV. • Regions that develop first [medulla oblongata (MD)] are defined by relatively high mitochondrial, metabolic and antioxidant function contributing to neuroprotection, compared to vulnerable areas such as FC, HC, and striatum (ST), that develop later, providing the biological basis for the "last in first out" hypothesis of ageing. [ABSTRACT FROM AUTHOR] more...
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- 2022
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12. Mitochondrial measures in neuronally enriched extracellular vesicles predict brain and retinal atrophy in multiple sclerosis.
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Ladakis, Dimitrios C, Yao, Pamela J, Vreones, Michael, Blommer, Joseph, Kalaitzidis, Grigorios, Sotirchos, Elias S, Fitzgerald, Kathryn C, Saidha, Shiv, Calabresi, Peter A, Kapogiannis, Dimitrios, and Bhargava, Pavan more...
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CEREBRAL atrophy , *EXTRACELLULAR vesicles , *MULTIPLE sclerosis , *MITOCHONDRIA , *OPTICAL coherence tomography - Abstract
Background: Mitochondrial dysfunction plays an important role in multiple sclerosis (MS) disease progression. Plasma extracellular vesicles are a potential source of novel biomarkers in MS, and some of these are derived from mitochondria and contain functional mitochondrial components. Objective: To evaluate the relationship between levels of mitochondrial complex IV and V activity in neuronally enriched extracellular vesicles (NEVs) and brain and retinal atrophy as assessed using serial magnetic resonance imaging (MRI) and optical coherence tomography (OCT). Methods: Our cohort consisted of 48 people with MS. NEVs were immunocaptured from plasma and mitochondrial complex IV and V activity levels were measured. Subjects underwent OCT every 6 months and brain MRI annually. The associations between baseline mitochondrial complex IV and V activities and brain substructure and retinal thickness changes were estimated utilizing linear mixed-effects models. Results: We found that higher mitochondrial complex IV activity and lower mitochondrial complex V activity levels were significantly associated with faster whole-brain volume atrophy. Similar results were found with other brain substructures and retinal layer atrophy. Conclusion: Our results suggest that mitochondrial measures in circulating NEVs could serve as potential biomarkers of disease progression and provide the rationale for larger follow-up longitudinal studies. [ABSTRACT FROM AUTHOR] more...
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- 2022
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13. Mitochondria-targeted hydrogen sulfide donors versus acute oxidative gastric mucosal injury.
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Magierowska, Katarzyna, Korbut, Edyta, Wójcik-Grzybek, Dagmara, Bakalarz, Dominik, Sliwowski, Zbigniew, Cieszkowski, Jakub, Szetela, Małgorzata, Torregrossa, Roberta, Whiteman, Matthew, and Magierowski, Marcin more...
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HYDROGEN sulfide , *ANNEXINS , *MTOR protein , *BLOOD flow , *LABORATORY rats , *PROTEIN expression - Abstract
Hydrogen sulfide (H 2 S) as a gaseous molecule prevents gastrointestinal (GI)-tract against various injuries. This study aimed to evaluate for the first time the detailed molecular mechanism of mitochondria-targeting H 2 S-prodrugs, AP39 and RT01 in gastroprotection against ischemia/reperfusion (I/R)-induced lesions. Wistar rats exposed to I/R were pretreated i.g. with vehicle, AP39 (0.004–2 mg/kg), RT01 (0.1 mg/kg), or with AP219 (0.1 mg/kg) as structural control without ability to release H 2 S. AP39 was also administered with mTOR1 inhibitor, rapamycin (1 mg/kg i.g.). Gastric damage area was assessed micro−/macroscopically, gastric blood flow (GBF) by laser flowmetry, mRNA level of HIF-1α, GPx, SOD1, SOD2, annexin-A1, SOCS3, IL-1RA, IL-1β, IL-1R1, IL-1R2, TNFR2, iNOS by real-time PCR. Gastric mucosal and/or serum content of IL-1β, IL-4, IL-5, IL-10, G-CSF, M-CSF, VEGFA, GRO, RANTES, MIP-1α, MCP1, TNF-α, TIMP1, FABP3, GST-α, STAT3/5 and phosphorylation of mTOR, NF-κB, ERK, Akt was evaluated by microbeads-fluorescent assay. Mitochondrial complexes activities were measured biochemically. RNA damage was assessed as 8-OHG by ELISA. AP39 and RT01 reduced micro−/macroscopic gastric I/R-injury increasing GBF. AP39-gastroprotection was accompanied by maintained activity of mitochondrial complexes, prevented RNA oxidation and enhanced mRNA/protein expression of SOCS3, IL-1RA, annexin-A1, GST-α, HIF-1α. Rapamycin reversed AP-39-gastroprotection. AP39-gastroprotection was followed by decreased NF-κB, ERK, IL-1β and enhanced Akt and mTOR proteins phosphorylation. AP39-prevented gastric mucosal damage caused by I/R-injury, partly by mitochondrial complex activity maintenance. AP39-mediated attenuation of gastric mucosal oxidation, hypoxia and inflammation involved mTOR1 and Akt pathways activity and modulation of HIF-1α, GST-α, SOCS3, IL1RA and TIMP1 molecular interplay. [Display omitted] [ABSTRACT FROM AUTHOR] more...
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- 2022
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14. New insights into the role of mitochondrial respiration in macrophage functions
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Gobelli, Dino Joaquín, Fuente García, Miguel Ángel de la, Simarro Grande, María, Gobelli, Dino Joaquín, Fuente García, Miguel Ángel de la, and Simarro Grande, María
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Escuela de Doctorado, Doctorado en Investigación Biomédica
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- 2024
15. Oxidative damage and mitochondrial functionality in hearts from KO UCP3 mice housed at thermoneutrality.
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Napolitano, Gaetana, Fasciolo, Gianluca, Magnacca, Nunzia, Goglia, Fernando, Lombardi, Assunta, and Venditti, Paola
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The antioxidant role of mitochondrial uncoupling protein 3 (UCP3) is controversial. This work aimed to investigate the effects of UCP3 on the heart of mice housed at thermoneutral temperature, an experimental condition that avoids the effects of thermoregulation on mitochondrial activity and redox homeostasis, preventing the alterations related to these processes from confusing the results caused by the lack of UCP3. WT and KO UCP3 mice were acclimatized at 30 °C for 4 weeks and hearts were used to evaluate metabolic capacity and redox state. Tissue and mitochondrial respiration, the activities of the mitochondrial complexes, and the protein expression of mitochondrial complexes markers furnished information on mitochondrial functionality. The levels of lipid and protein oxidative damage markers, the activity of antioxidant enzymes, the reactive oxygen species levels, and the susceptibility to in vitro Fe-ascorbate-induced oxidative stress furnished information on redox state. UCP3 ablation reduced tissue and mitochondrial respiratory capacities, not affecting the mitochondrial content. In KO UCP3 mice, the mitochondrial complexes activities were lower than in WT without changes in their content. These effects were accompanied by an increase in the level of oxidative stress markers, ROS content, and in vitro susceptibility to oxidative stress, notwithstanding that the activities of antioxidant enzymes were not affected by UCP3 ablation. Such modifications are also associated with enhanced activation/phosphorylation of EIF2α, a marker of integrated stress response and endoplasmic reticulum stress (GRP778 BIP). The lack of UCP3 makes the heart more prone to oxidative insult by reducing oxygen consumption and increasing ROS. Our results demonstrate that UCP3 helps the cell to preserve mitochondrial function by mitigating oxidative stress. [ABSTRACT FROM AUTHOR] more...
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- 2022
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16. Spermidine Regulates Mitochondrial Function by Enhancing eIF5A Hypusination and Contributes to Reactive Oxygen Species Production and Ganoderic Acid Biosynthesis in Ganoderma lucidum.
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Xiaofei Han, Jiaolei Shangguan, Zi Wang, Yu Li, Junpei Fan, Ang Ren, and Mingwen Zhao
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ORNITHINE decarboxylase , *GANODERMA lucidum , *REACTIVE oxygen species , *SPERMIDINE , *MITOCHONDRIA , *BIOSYNTHESIS , *TRP channels - Abstract
Spermidine, a kind of polycation and one important member of the polyamine family, is essential for survival in many kinds of organisms and participates in the regulation of cell growth and metabolism. To explore the mechanism by which spermidine regulates ganoderic acid (GA) biosynthesis in Ganoderma lucidum, the effects of spermidine on GA and reactive oxygen species (ROS) contents were examined. Our data suggested that spermidine promoted the production of mitochondrial ROS and positively regulated GA biosynthesis. Further research revealed that spermidine promoted the translation of mitochondrial complexes I and II and subsequently influenced their activity. With a reduction in eukaryotic translation initiation factor 5A (eIF5A) hypusination by over 50% in spermidine synthase gene (spds) knockdown strains, the activities of mitochondrial complexes I and II were reduced by nearly 60% and 80%, respectively, and the protein contents were reduced by over 50%, suggesting that the effect of spermidine on mitochondrial complexes I and II was mediated through its influence on eIF5A hypusination. Furthermore, after knocking down eIF5A, the deoxyhypusine synthase gene (dhs), and the deoxyhypusine hydroxylase gene (dohh), the mitochondrial ROS level was reduced by nearly 50%, and the GA content was reduced by over 40%, suggesting that eIF5A hypusination contributed to mitochondrial ROS production and GA biosynthesis. In summary, spermidine maintains mitochondrial ROS homeostasis by regulating the translation and subsequent activity of complexes I and II via eIF5A hypusination and promotes GA biosynthesis via mitochondrial ROS signaling. The present findings provide new insight into the spermidine-mediated biosynthesis of secondary metabolites. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
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17. The nature compound dehydrocrenatidine exerts potent antihepatocellular carcinoma by destroying mitochondrial complexes in vitro and in vivo.
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Hou, Zi‐Lin, Han, Feng‐Ying, Lou, Li‐Li, Zhao, Wen‐Yu, Huang, Xiao‐Xiao, Yao, Guo‐Dong, and Song, Shao‐Jiang
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Cumulative evidence indicates that mitochondria dysfunction plays an important role in tumour treatment. Given the limited efficacy and toxicity of current mitochondria‐targeted drugs, research into effective mitochondria‐targeted anticancer agents remains an irresistible general trend. In this study, it was found that dehydrocrenatidine (DEC), a β‐carbolin alkaloid isolated from Picrasma quassiodes, displays a promising growth inhibitory effect in vitro and in vivo by inducing apoptosis of hepatocellular carcinoma (HCC) cells. Mechanistically, we provided that the possible target of DEC against HCC cells was determined by isobaric labels for relative and absolute quantification assay and validated them using further experiments. The results suggested that DEC can target and regulate the function of mitochondrial complexes I, III and IV, affecting oxidative phosphorylation and ultimately leading to mitochondrial dysfunction to exert its anti‐HCC effects. In addition, the combination of DEC and sorafenib showed a synergistic effect and was also associated with mitochondrial dysfunction. Importantly, DEC did not show significant toxicity in mice. This study provided a new insight into underlying mechanisms in DEC‐treated HCC cells, suggesting that DEC might be a mitochondrial targeting lead compound. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
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18. Mitochondria: Muscle Morphology
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Sciacco, Monica, Fagiolari, Gigliola, Tironi, Roberto, Peverelli, Lorenzo, Moggio, Maurizio, Mancuso, Michelangelo, editor, and Klopstock, Thomas, editor
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- 2019
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19. Celecoxib decreases mitochondrial complex IV activity and induces oxidative stress in isolated rat heart mitochondria: An analysis for its cardiotoxic adverse effect.
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Atashbar, Saman, Jamali, Zhaleh, Khezri, Saleh, and Salimi, Ahmad
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CELECOXIB ,MITOCHONDRIA ,OXIDATIVE stress ,REACTIVE oxygen species ,RATS - Abstract
In spite of the cardiotoxic effect of selective cyclooxygenase‐2 inhibitors, they are most widely used as anti‐inflammatory and analgesic drugs. Today, valdecoxib and rofecoxib have been withdrawn in the market but celecoxib remains. In this study, we focused on an analysis of celecoxib toxic effects on isolated mitochondria. Isolated rat heart mitochondria were obtained using differential centrifugation. Using flow cytometry and biochemical assays, we searched succinate dehydrogenases, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) formation, mitochondrial swelling, ATP/ADP ratio, lipid peroxidation, and mitochondrial complexes activity in rat heart isolated mitochondria. Herein, our results indicated a significant decrease in the activity of complex IV after exposure with celecoxib (16 µg/ml). This decrease in the activity of complex IV is paralleled by the MMP collapse, ROS formation, mitochondrial swelling, depletion of ATP, and lipid peroxidation. For the first time, this introductory study has shown a significant decrease in the activity of complex IV and mitochondrial dysfunction after exposure with celecoxib in rat heart isolated mitochondria. [ABSTRACT FROM AUTHOR] more...
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- 2022
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20. Neuromuscular electrical stimulation resistance training enhances oxygen uptake and ventilatory efficiency independent of mitochondrial complexes after spinal cord injury: a randomized clinical trial.
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Gorgey, Ashraf S., Lai, Raymond E., Khalil, Refka E., Rivers, Jeannie, Cardozo, Christopher, Qun Chen, and Lesnefsky, Edward J.
- Abstract
The purpose of the study was to determine whether neuromuscular electrical stimulation resistance training (NMES-RT)-evoked muscle hypertrophy is accompanied by increased V̇o
2 peak, ventilatory efficiency, and mitochondrial respiration in individuals with chronic spinal cord injury (SCI). Thirty-three men and women with chronic, predominantly traumatic SCI were randomized to either NMES-RT (n = 20) or passive movement training (PMT; n = 13). Functional electrical stimulation-lower extremity cycling (FES-LEC) was used to test the leg V̇o2 peak, V̇E/V̇co2 ratio, and substrate utilization pre- and postintervention. Magnetic resonance imaging was used to measure muscle cross-sectional area (CSA). Finally, muscle biopsy was performed to measure mitochondrial complexes and respiration. The NMES-RT group showed a significant increase in postintervention V̇o2 peak compared with baseline (ΔV̇o2 = 14%, P < 0.01) with no changes in the PMT group (ΔV̇o2 = 1.6%, P = 0.47). Similarly, thigh (ΔCSAthigh = 19%) and knee extensor (ΔCSAknee = 30.4%, P < 0.01) CSAs increased following NMES-RT but not after PMT. The changes in thigh and knee extensor muscle CSAs were positively related with the change in V̇o2 peak. Neither NMES-RT nor PMT changed mitochondrial complex tissue levels; however, changes in peak V̇o2 were related to complex I. In conclusion, in persons with SCI, NMES-RT-induced skeletal muscle hypertrophy was accompanied by increased peak V̇o2 consumption which may partially be explained by enhanced activity of mitochondrial complex I. NEW & NOTEWORTHY Leg oxygen uptake (V̇o2 ) and ventilatory efficiency (V̇E/V̇co2 ratio) were measured during functional electrical stimulation cycling testing following 12-16 wk of either electrically evoked resistance training or passive movement training, and the respiration of mitochondrial complexes. Resistance training increased thigh muscle area and leg V̇o2 peak but decreased V̇E/V̇co2 ratio without changes in mitochondrial complex levels. Leg V̇o2 peak was associated with muscle hypertrophy and mitochondrial respiration of complex I following training. [ABSTRACT FROM AUTHOR] more...- Published
- 2021
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21. Cadmium-Induced Cytotoxicity: Effects on Mitochondrial Electron Transport Chain
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Jacopo Junio Valerio Branca, Alessandra Pacini, Massimo Gulisano, Niccolò Taddei, Claudia Fiorillo, and Matteo Becatti
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cadmium ,cytotoxicity ,mitochondria ,mitochondrial electron transport chain ,mitochondrial complexes ,Biology (General) ,QH301-705.5 - Abstract
Cadmium (Cd) is a well-known heavy metal and environmental toxicant and pollutant worldwide, being largely present in every kind of item such as plastic (toys), battery, paints, ceramics, contaminated water, air, soil, food, fertilizers, and cigarette smoke. Nowadays, it represents an important research area for the scientific community mainly for its effects on public health. Due to a half-life ranging between 15 and 30 years, Cd owns the ability to accumulate in organs and tissues, exerting deleterious effects. Thus, even at low doses, a Cd prolonged exposure may cause a multiorgan toxicity. Mitochondria are key intracellular targets for Cd-induced cytotoxicity, but the underlying mechanisms are not fully elucidated. The present review is aimed to clarify the effects of Cd on mitochondria and, particularly, on the mitochondrial electron transport chain. more...
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- 2020
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22. Mitochondrial dysfunction in CA1 hippocampal neurons of the UBE3A deficient mouse model for Angelman syndrome
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Su, Hailing, Fan, Weiwei, Coskun, Pinar E, Vesa, Jouni, Gold, June-Anne, Jiang, Yong-Hui, Potluri, Prasanth, Procaccio, Vincent, Acab, Allan, Weiss, John H, Wallace, Douglas C, and Kimonis, Virginia E more...
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Pediatric ,Intellectual and Developmental Disabilities (IDD) ,Neurosciences ,Rare Diseases ,Brain Disorders ,2.1 Biological and endogenous factors ,Neurological ,Angelman Syndrome ,Animals ,CA1 Region ,Hippocampal ,Disease Models ,Animal ,Female ,Genotype ,Male ,Mice ,Mice ,Knockout ,Mice ,Transgenic ,Mitochondria ,Neurons ,Purkinje Cells ,Synaptic Vesicles ,Ubiquitin-Protein Ligases ,Angelman syndrome ,Mitochondrial complexes ,Synaptic vesicle ,Electron microscopy ,UBE3A deficient mouse ,Psychology ,Cognitive Sciences ,Biochemistry and cell biology ,Biological psychology - Abstract
Angelman syndrome (AS) is a severe neurological disorder caused by a deficiency of ubiquitin protein ligase E3A (UBE3A), but the pathophysiology of the disease remains unknown. We now report that in the brains of AS mice in which the maternal UBE3A allele is mutated (m-) and the paternal allele is potentially inactivated by imprinting (p+) (UBE3A m-\p+), the mitochondria are abnormal and exhibit a partial oxidative phosphorylation (OXPHOS) defect. Electron microscopy of the hippocampal region of the UBE3A m-\p+ mice (n=6) reveals small, dense mitochondria with altered cristae, relative to wild-type littermates (n=6) and reduced synaptic vesicle density. The specific activity of OXPHOS complex III is reduced in whole brain mitochondria in UBE3A m-\p+ (n=5) mice versus wild-type littermates (n=5). Therefore, mitochondrial dysfunction may contribute to the pathophysiology of Angelman syndrome. more...
- Published
- 2011
23. Recurrent inhibition of mitochondrial complex III induces chronic pulmonary vasoconstriction and glycolytic switch in the rat lung
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Olga Rafikova, Anup Srivastava, Ankit A. Desai, Ruslan Rafikov, and Stevan P. Tofovic
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Pulmonary hypertension ,Glycolytic switch ,Mitochondrial complexes ,Protein nitration ,Metabolomics ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Pulmonary arterial hypertension (PAH) is a fatal disease; however, the mechanisms directly involved in triggering and the progression of PAH are not clear. Based on previous studies that demonstrated a possible role of mitochondrial dysfunction in the pathogenesis of PAH, we investigated the effects of chronic inhibition of mitochondrial function in vivo in healthy rodents. Methods Right ventricle systolic pressure (RVSP) was measured in female rats at baseline and up to 24 days after inhibition of mitochondrial respiratory Complex III, induced by Antimycin A (AA, 0.35 mg/kg, given three times starting at baseline and then days 3 and 6 as a bolus injection into the right atrial chamber). Results Rodents exposed to AA demonstrated sustained increases in RVSP from days 6 through 24. AA-exposed rodents also possessed a progressive increase in RV end-diastolic pressure but not RV hypertrophy, which may be attributed to either early stages of PAH development or to reduced RV contractility due to inhibition of myocardial respiration. Protein nitration levels in plasma were positively correlated with PAH development in AA-treated rats. This finding was strongly supported by results obtained from PAH humans where plasma protein nitration levels were correlated with markers of PAH severity in female but not male PAH patients. Based on previously reported associations between increased nitric oxide production levels with female gender, we speculate that in females with PAH mitochondrial dysfunction may represent a more deleterious form, in part, due to an increased nitrosative stress development. Indeed, the histological analysis of AA treated rats revealed a strong perivascular edema, a marker of pulmonary endothelial damage. Finally, AA treatment was accompanied by a severe metabolic shift toward glycolysis, a hallmark of PAH pathology. Conclusions Chronic mitochondrial dysfunction induces the combination of vascular damage and metabolic reprogramming that may be responsible for PAH development. This mechanism may be especially important in females, perhaps due to an increased NO production and nitrosative stress development. more...
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- 2018
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24. Impairment of Mitochondrial Redox Status in Peripheral Lymphocytes of Multiple Sclerosis Patients
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Hugo Gonzalo, Lara Nogueras, Anna Gil-Sánchez, José Vicente Hervás, Petya Valcheva, Cristina González-Mingot, Meritxell Martin-Gari, Marc Canudes, Silvia Peralta, Maria José Solana, Reinald Pamplona, Manuel Portero-Otin, Jordi Boada, Jose Carlos Enrique Serrano, and Luis Brieva more...
- Subjects
multiple sclerosis ,oxidative stress ,mitochondria ,superoxide anion ,mitochondrial complexes ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Literature suggests that oxidative stress (OS) may be involved in the pathogenesis of multiple sclerosis (MS), in which the immune system is known to play a key role. However, to date, the OS in peripheral lymphocytes and its contribution to the disease remain unknown. The aim of the present study was to explore the influence of OS in peripheral lymphocytes of MS patients. To that end, a cross-sectional, observational pilot study was conducted [n = 58: 34 MS and 24 healthy subjects (control group)]. We have measured superoxide production and protein mitochondrial complex levels in peripheral blood mononuclear cells (PBMCs) isolated from MS patients and control. Lactate levels and the antioxidant capacity were determined in plasma. We adjusted the comparisons between study groups by age, sex and cell count according to case. Results demonstrated that PBMCs, specifically T cells, from MS patients exhibited significantly increased superoxide anion production compared to control group (p = 0.027 and p = 0.041, respectively). Increased superoxide production in PBMCs was maintained after the adjustment (p = 0.044). Regarding mitochondrial proteins, we observe a significant decrease in the representative protein content of the mitochondrial respiratory chain complexes I-V in PBMCs of MS patients (p = 0.002, p = 0.037, p = 0.03, p = 0.044, and p = 0.051, respectively), which was maintained for complexes I, III, and V after the adjustment (p = 0.026; p = 0.033; p = 0.033, respectively). In MS patients, a trend toward increased plasma lactate concentration was detected [8.04 mg lactate/dL (5.25, 9.49) in the control group, 11.36 mg lactate/dL (5.41, 14.81) in MS patients] that was statistically significant after the adjustment (p = 0.013). This might be indicative of compromised mitochondrial function. Finally, antioxidant capacity was also decreased in plasma from MS patients, both before (p = 0.027) and after adjusting for sex and age (p = 0.006). Our findings demonstrate that PBMCs of MS patients show impaired mitochondrial redox status and deficient antioxidant capacity. These results demonstrate for the first time the existence of mitochondrial alterations in the cells immune cells of MS patients already at the peripheral level. more...
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- 2019
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25. Impairment of Mitochondrial Redox Status in Peripheral Lymphocytes of Multiple Sclerosis Patients.
- Author
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Gonzalo, Hugo, Nogueras, Lara, Gil-Sánchez, Anna, Hervás, José Vicente, Valcheva, Petya, González-Mingot, Cristina, Martin-Gari, Meritxell, Canudes, Marc, Peralta, Silvia, Solana, Maria José, Pamplona, Reinald, Portero-Otin, Manuel, Boada, Jordi, Serrano, Jose Carlos Enrique, and Brieva, Luis more...
- Subjects
SUPEROXIDES ,MULTIPLE sclerosis ,GERM cells ,LYMPHOCYTES ,MITOCHONDRIAL proteins ,OXIDANT status - Abstract
Literature suggests that oxidative stress (OS) may be involved in the pathogenesis of multiple sclerosis (MS), in which the immune system is known to play a key role. However, to date, the OS in peripheral lymphocytes and its contribution to the disease remain unknown. The aim of the present study was to explore the influence of OS in peripheral lymphocytes of MS patients. To that end, a cross-sectional, observational pilot study was conducted [ n = 58: 34 MS and 24 healthy subjects (control group)]. We have measured superoxide production and protein mitochondrial complex levels in peripheral blood mononuclear cells (PBMCs) isolated from MS patients and control. Lactate levels and the antioxidant capacity were determined in plasma. We adjusted the comparisons between study groups by age, sex and cell count according to case. Results demonstrated that PBMCs, specifically T cells, from MS patients exhibited significantly increased superoxide anion production compared to control group (p = 0.027 and p = 0.041, respectively). Increased superoxide production in PBMCs was maintained after the adjustment (p = 0.044). Regarding mitochondrial proteins, we observe a significant decrease in the representative protein content of the mitochondrial respiratory chain complexes I-V in PBMCs of MS patients (p = 0.002, p = 0.037, p = 0.03, p = 0.044, and p = 0.051, respectively), which was maintained for complexes I, III, and V after the adjustment (p = 0.026; p = 0.033; p = 0.033, respectively). In MS patients, a trend toward increased plasma lactate concentration was detected [8.04 mg lactate/dL (5.25, 9.49) in the control group, 11.36 mg lactate/dL (5.41, 14.81) in MS patients] that was statistically significant after the adjustment (p = 0.013). This might be indicative of compromised mitochondrial function. Finally, antioxidant capacity was also decreased in plasma from MS patients, both before (p = 0.027) and after adjusting for sex and age (p = 0.006). Our findings demonstrate that PBMCs of MS patients show impaired mitochondrial redox status and deficient antioxidant capacity. These results demonstrate for the first time the existence of mitochondrial alterations in the cells immune cells of MS patients already at the peripheral level. [ABSTRACT FROM AUTHOR] more...
- Published
- 2019
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26. Caffeic Acid Phenethyl Ester Protects Kidney Mitochondria against Ischemia/Reperfusion Induced Injury in an In Vivo Rat Model
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Justina Kamarauskaite, Rasa Baniene, Darius Trumbeckas, Arvydas Strazdauskas, and Sonata Trumbeckaite
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kidney ,caffeic acid phenethyl ester ,antioxidant ,mitochondria ,ischemia/reperfusion ,mitochondrial complexes ,Therapeutics. Pharmacology ,RM1-950 - Abstract
To improve ischemia/reperfusion tolerance, a lot of attention has been focused on natural antioxidants. Caffeic acid phenethyl ester (CAPE), an active component of the resinous exudates of the buds and young leaves of Populus nigra L., Baccharis sarothroides A., etc., and of propolis, possesses unique biological activities such as anti-inflammatory, antioxidant, immunomodulating, and cardioprotective effects, among others. There is a lack of studies showing a link between the antioxidant potential of CAPE and the mechanism of protective action of CAPE at the level of mitochondria, which produces the main energy for the basic functions of the cell. In the kidney, ischemia/reperfusion injury contributes to rapid kidney dysfunction and high mortality rates, and the search for biologically active protective compounds remains very actual. Therefore, the aim of this study was to identify the antioxidant potential of CAPE and to investigate whether CAPE can protect rat kidney mitochondria from in vivo kidney ischemia/reperfusion induced injury. We found that CAPE (1) possesses antioxidant activity (the reducing properties of CAPE are more pronounced than its antiradical properties); CAPE effectively reduces cytochrome c; (2) protects glutamate/malate oxidation and Complex I activity; (3) preserves the mitochondrial outer membrane from damage and from the release of cytochrome c; (4) inhibits reactive oxygen species (ROS) generation in the Complex II (SDH) F site; (5) diminishes ischemia/reperfusion-induced LDH release and protects from necrotic cell death; and (6) has no protective effects on succinate oxidation and on Complex II +III activity, but partially protects Complex II (SDH) from ischemia/reperfusion-induced damage. In summary, our study shows that caffeic acid phenethyl ester protects kidney mitochondrial oxidative phosphorylation and decreases ROS generation at Complex II in an in vivo ischemia/reperfusion model, and shows potential as a therapeutic agent for the development of pharmaceutical preparations against oxidative stress-related diseases. more...
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- 2021
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27. Comparison of the effects of MnO2-NPs and MnO2-MPs on mitochondrial complexes in different organs.
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Ashrafi Hafez, Asghar, Naserzadeh, Parvaneh, Mortazavian, Amir Mohammad, Mehravi, Bita, Ashtari, Khadijeh, Seydi, Enayatollah, and Salimi, Ahmad
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- *
ENZYME-linked immunosorbent assay , *SUCCINATE dehydrogenase , *OXIDANT status , *MANGANESE oxides - Abstract
Today, nanoparticles (NPs) have been widely used in various fields. Manganese oxide nanoparticles have attracted a lot of attention due to many applications. One of the major concerns regarding the widespread use of various NPs is the exposure and accumulation in human organs and finally toxicity. The generation of reactive oxygen species (ROS) by mitochondria is one of the most important mechanisms of toxicity suggested by published studies induced by other NPs. However, limited studies have been conducted on the mechanism of toxicity of MnO2-NPs and MnO2-microparticles (MnO2-MPs). In this study, we compared the accumulation of MnO2-NPs and MnO2-MPs in different tissues and evaluated their effects on mitochondrial complexes in isolated mitochondria. Our results showed that intravascular (iv) administration of the MnO2-NPs in the same dose compared to the MnO2-MPs resulted in more accumulation in the C57 mouse female tissues. The effect of MnO2-NPs and MnO2-MPs in mitochondria showed that complexes I and III play an important role in increasing ROS generation and this effect is related to type of tissue. Also, our results showed that exposure to MnO2-NPs and MnO2-MPs reduced the activity of mitochondrial complexes II and IV. Our results suggest that the toxicity of the MnO2-NPs is higher than that of the MnO2-MPs and can lead to the depletion of antioxidant status, likely induction of apoptosis, cancer, and neurodegenerative disease. Abbreviations: NPs: nanoparticles; ROS: reactive oxygen species; SDH: succinate dehydrogenase; DCFH-DA: dichloro-dihydro-fluorescein diacetate; ELISA: enzyme-linked immunosorbent assay; MnO2-NPs: manganese oxide nanoparticles [ABSTRACT FROM AUTHOR] more...
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- 2019
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28. Depressed mitochondrial function and electron transport Complex II-mediated H2O2 production in the cortex of type 1 diabetic rodents.
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Roy Chowdhury, Subir, Djordjevic, Jelena, Thomson, Ella, Smith, Darrell R., Albensi, Benedict C., and Fernyhough, Paul
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- *
MITOCHONDRIAL pathology , *DIABETES complications , *ELECTRON transport , *PHYSIOLOGICAL effects of hydrogen peroxide , *LABORATORY rodents - Abstract
Aims Abnormalities in mitochondrial function under diabetic conditions can lead to deficits in function of cortical neurons and their support cells exhibiting a pivotal role in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. We aimed to assess mitochondrial respiration rates and membrane potential or H 2 O 2 generation simultaneously and expression of proteins involved in mitochondrial dynamics, ROS scavenging and AMPK/SIRT/PGC-1α pathway activity in cortex under diabetic conditions. Methods Cortical mitochondria from streptozotocin (STZ)-induced type 1 diabetic rats or mice, and aged-matched controls were used for simultaneous measurements of mitochondrial respiration rates and mitochondrial membrane potential (mtMP) or H 2 O 2 using OROBOROS oxygraph. Measurements of enzymatic activities of respiratory complexes were performed using spectophotometry. Protein levels in cortical mitochondria and homogenates were determined by Western blotting. Results Mitochondrial coupled respiration rates and FCCP-induced uncoupled respiration rates were significantly decreased in mitochondria of cortex of STZ-diabetic rats compared to controls. The mtMP in the presence of ADP was significantly depolarized and succinate-dependent respiration rates and H 2 O 2 were significantly diminished in cortical mitochondria of diabetic animals compared to controls, accompanied with reduced expression of CuZn- and Mn-superoxide dismutase. The enzymatic activities of Complex I, II, and IV and protein levels of certain components of Complex I and II, mitofusin 2 (Mfn2), dynamin-related protein 1 (DRP1), P-AMPK, SIRT2 and PGC-1α were significantly diminished in diabetic cortex. Conclusion Deficits in mitochondrial function, dynamics, and antioxidant capabilities putatively mediated through sub-optimal AMPK/SIRT/PGC-1α signaling, are involved in the development of early sub-clinical neurodegeneration in the cortex under diabetic conditions. [ABSTRACT FROM AUTHOR] more...
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- 2018
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29. The beneficial role of Naringin- a citrus bioflavonoid, against oxidative stress-induced neurobehavioral disorders and cognitive dysfunction in rodents: A systematic review and meta-analysis.
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Viswanatha, Gollapalle Lakshminarayanashastry, Shylaja, H., and Moolemath, Yogananda
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- *
NARINGIN , *FLAVONOID glycosides , *NEUROBEHAVIORAL disorders , *RODENT physiology , *LIPID peroxidation (Biology) - Abstract
Objectives Naringin is a bioflavonoid, very abundantly found in citrus species. In literature, naringin has been scientifically well documented for its beneficial effects in various neurological disorders. In this systematic review and meta-analysis, we have made an attempt to correlate the protective role of naringin against oxidative stress-induced neurological disorders in rodents. Methods The systematic search was performed using electronic databases; the search was mainly focused on the role of naringin in oxidative stress-induced neuropathological conditions in rodents. While, the meta-analysis was performed on the effect of naringin on oxidative stress markers [superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), reduced glutathione (GSH), lipid peroxidation (LPO)], nitrite, mitochondrial complexes (I to IV) and enzymes (acetylcholinesterase, Na + -K + -ATPase, Ca 2+ -ATPase, and Mg 2+ -ATPase) in the rodent brain. The data was analyzed using Review Manager Software. The results Based on the inclusion and exclusion criteria, twenty studies were selected. The meta-analysis revealed that, naringin could significantly inhibit various physical and chemical stimuli- induced neurological perturbances in the rodent brain, mediated through oxidative stress. Further, naringin also significantly restored the levels of all the oxidative stress markers (oxidative, nitrosative, enzymes, and mitochondrial complexes) in different parts of the rodent brain. Summary This systematic review and meta-analysis supports the available scientific evidence on the beneficial role of naringin in the management of various neurological ailments. However, further studies involving human subjects is recommended to establish the safety and therapeutic efficacy in humans. [ABSTRACT FROM AUTHOR] more...
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- 2017
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30. The conditional mitochondrial protein complexome in the Arabidopsis thaliana root and shoot.
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Zhang Y, Jaime SM, Bulut M, Graf A, and Fernie AR
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- Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Vitamin K 3 pharmacology, Vitamin K 3 metabolism, Citric Acid Cycle physiology, Arabidopsis genetics, Arabidopsis metabolism, Arabidopsis Proteins genetics, Arabidopsis Proteins metabolism
- Abstract
Protein complexes are important for almost all biological processes. Hence, to fully understand how cells work, it is also necessary to characterize protein complexes and their dynamics in response to various cellular cues. Moreover, the dynamics of protein interaction play crucial roles in regulating the (dis)association of protein complexes and, in turn, regulating biological processes such as metabolism. Here, mitochondrial protein complexes were investigated by blue native PAGE and size-exclusion chromatography under conditions of oxidative stress in order to monitor their dynamic (dis)associations. Rearrangements of enzyme interactions and changes in protein complex abundance were observed in response to oxidative stress induced by menadione treatment. These included changes in enzymatic protein complexes involving γ-amino butyric acid transaminase (GABA-T), Δ-ornithine aminotransferase (Δ-OAT), or proline dehydrogenase 1 (POX1) that are expected to affect proline metabolism. Menadione treatment also affected interactions between several enzymes of the tricarboxylic acid (TCA) cycle and the abundance of complexes of the oxidative phosphorylation pathway. In addition, we compared the mitochondrial complexes of roots and shoots. Considerable differences between the two tissues were observed in the mitochondrial import/export apparatus, the formation of super-complexes in the oxidative phosphorylation pathway, and specific interactions between enzymes of the TCA cycle that we postulate may be related to the metabolic/energetic requirements of roots and shoots., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2023
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31. Iron Depletion Affects Genes Encoding Mitochondrial Electron Transport Chain and Genes of NonOxidative Metabolism, Pyruvate Kinase and Lactate Dehydrogenase, in Primary Human Cardiac Myocytes Cultured upon Mechanical Stretch
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Magdalena Dziegala, Kamil A. Kobak, Monika Kasztura, Jacek Bania, Krystian Josiak, Waldemar Banasiak, Piotr Ponikowski, and Ewa A. Jankowska
- Subjects
mitochondrial complexes ,oxidative metabolism ,non-oxidative metabolism ,iron deficiency ,iron excess ,human cardiomyocytes ,Cytology ,QH573-671 - Abstract
(1) Background: Oxidative energy metabolism is presumed to rely on the optimal iron supply. Primary human cardiac myocytes (HCM) exposed to different iron availability conditions during mechanical stretch are anticipated to demonstrate expression changes of genes involved in aerobic and anaerobic metabolic pathways. (2) Methods: HCM were cultured for 48 h either in static conditions and upon mechanical stretch at the optimal versus reduced versus increased iron concentrations. We analyzed the expression of pyruvate kinase (PKM2), lactate dehydrogenase A (LDHA), and mitochondrial complexes I–V at the mRNA and protein levels. The concentration of l-lactate was assessed by means of lactate oxidase method-based kit. (3) Results: Reduced iron concentrations during mechanical work caused a decreased expression of complexes I–V (all p < 0.05). The expression of PKM2 and LDHA, as well as the medium concentration of l-lactate, was increased in these conditions (both p < 0.05). HCM exposed to the increased iron concentration during mechanical effort demonstrated a decreased expression of mitochondrial complexes (all p < 0.01); however, a decrement was smaller than in case of iron chelation (p < 0.05). The iron-enriched medium caused a decrease in expression of LDHA and did not influence the concentration of l-lactate. (4) Conclusions: During mechanical effort, the reduced iron availability enhances anaerobic glycolysis and extracellular lactate production, whilst decreasing mitochondrial aerobic pathway in HCM. Iron enrichment during mechanical effort may be protective in the context of intracellular protein machinery of non-oxidative metabolism with no effect on the extracellular lactate concentration. more...
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- 2018
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32. Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment.
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Golpich, Mojtaba, Amini, Elham, Mohamed, Zahurin, Azman Ali, Raymond, Mohamed Ibrahim, Norlinah, and Ahmadiani, Abolhassan
- Subjects
- *
TREATMENT of neurodegeneration , *MITOCHONDRIAL pathology , *ORIGIN of life , *TARGETED drug delivery , *MITOCHONDRIAL physiology - Abstract
Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system ( CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological-based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease ( AD), Parkinson's disease ( PD), Huntington's disease ( HD), and amyotrophic lateral sclerosis ( ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain ( ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases. [ABSTRACT FROM AUTHOR] more...
- Published
- 2017
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33. Naringin and Sertraline Ameliorate Doxorubicin-Induced Behavioral Deficits Through Modulation of Serotonin Level and Mitochondrial Complexes Protection Pathway in Rat Hippocampus.
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Kwatra, Mohit, Jangra, Ashok, Mishra, Murli, Sharma, Yogita, Ahmed, Sahabuddin, Ghosh, Pinaki, Kumar, Vikas, Vohora, Divya, and Khanam, Razia
- Subjects
- *
NARINGIN , *SERTRALINE , *DOXORUBICIN , *SEROTONIN , *BEHAVIOR disorders , *HIPPOCAMPUS (Brain) , *LABORATORY rats , *DISEASE risk factors - Abstract
The present study was designed to investigate the neuroprotective effect of naringin (NR) alone as well as its combination with sertraline (SRT) against doxorubicin (DOX)-induced neurobehavioral and neurochemical anomalies. DOX (15 mg/kg; i.p.) administration caused behavioral alterations, oxidative stress, neuroinflammation, mitochondrial dysfunction and monoamines alteration in male Wistar rats. NR (50 and 100 mg/kg; i.p.) and SRT (5 mg/kg; i.p.) treatment significantly attenuated DOX-induced anxiety and depressive-like behavior as evident from elevated plus maze (EPM) and modified forced swimming test (mFST), respectively. NR treatment significantly attenuated DOX-induced raised plasma corticosterone (CORT), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in the hippocampus (HC). Furthermore, we found that combination of NR and SRT regimen ameliorated DOX-induced behavioral anomalies through modulation of the 5-HT level and mitochondrial complexes protection pathway along with alleviation of oxidative stress in the HC region. Therefore, NR treatment alone or in combination with SRT could be beneficial against DOX-induced neurotoxicity. [ABSTRACT FROM AUTHOR] more...
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- 2016
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34. Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats.
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Kwatra, Mohit, Kumar, Vikas, Jangra, Ashok, Mishra, Murli, Ahmed, Sahabuddin, Ghosh, Pinaki, Vohora, Divya, and Khanam, Razia
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- *
NARINGIN , *CARDIOTOXICITY , *DOXORUBICIN , *DRUG therapy , *LABORATORY rats , *INTRAPERITONEAL injections - Abstract
Context: Doxorubicin (Dox) is one of the most active chemotherapeutic agents used to treat various types of cancers. Its clinical utility is compromised due to fatal cardiac toxicity characterized by an irreversible cardiomyopathy. Objective: This study evaluates the cardioprotective potential of naringin (NR) against Dox-induced acute cardiac toxicity in rats. Materials and methods: Male Wistar rats were randomly divided into five groups. NR (50 and 100 mg/kg) was administered intraperitoneally (i.p.) daily from 0 to 14 d. Doxorubicin (15 mg/kg, i.p.) was given as a single dose on the 10th day. On the 14th day, all animals were sacrificed and oxidative stress parameters that include malondialdehyde (MDA), glutathione (GSH) level, superoxide dismutase (SOD), catalase (CAT) activities, and all mitochondrial complexes (I-IV) activities were evaluated along with histopathological studies of the heart. Results: Doxorubicin-induced cardiotoxicity was confirmed by increased (p < 0.05) MDA, decreased (p < 0.05) GSH levels, SOD, and CAT activities, mitochondrial complexes (I–IV) activities in the heart tissue. NR (100 mg/kg) showed cardioprotection as evident from significant decreased MDA (p < 0.001) level, raised (p < 0.001) GSH level, SOD and CAT activities and increased mitochondrial complexes I (p < 0.01), II (p < 0.001), III (p < 0.001), and IV (p < 0.05) activities. Further, Dox-induced cardiotoxicity was confirmed by histopathological studies. These obtained results indicated the protective role of NR against Dox-induced cardiac toxicity in rats. Conclusion: NR can be used in combination with Dox due to its high cardioprotective effect against Dox-induced cardiomyopathy. [ABSTRACT FROM AUTHOR] more...
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- 2016
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35. Neuroprotective activities of curcumin and quercetin with potential relevance to mitochondrial dysfunction induced by oxaliplatin.
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Waseem, Mohammad and Parvez, Suhel
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- *
CURCUMIN , *QUERCETIN , *OXALIPLATIN , *OXIDATIVE stress , *BIOMARKERS , *FUNCTIONAL foods - Abstract
Peripheral neurotoxicity is one of the serious dose-limiting side effects of oxaliplatin (Oxa) when used in the treatment of malignant conditions. It is documented that it elicits major side effects specifically neurotoxicity due to oxidative stress forcing the patients to limit its clinical use in long-term treatment. Oxidative stress has been proven to be involved in Oxa-induced toxicity including neurotoxicity. The mitochondria have recently emerged as targets for anticancer drugs in various kinds of toxicity including neurotoxicity that can lead to neoplastic disease. However, there is paucity of literature involving the role of the mitochondria in mediating Oxa-induced neurotoxicity and its underlying mechanism is still debatable. The purpose of this study was to investigate the dose-dependent damage caused by Oxa on isolated brain mitochondria under in vitro conditions. The study was also designed to investigate the neuroprotective effects of nutraceuticals, curcumin (CMN), and quercetin (QR) on Oxa-induced mitochondrial oxidative stress and respiratory chain complexes in the brain of rats. Oxidative stress biomarkers, levels of nonenzymatic antioxidants, activities of enzymatic antioxidants, and mitochondrial complexes were evaluated against the neurotoxicity induced by Oxa. Pretreatment with CMN and QR significantly replenished the mitochondrial lipid peroxidation levels and protein carbonyl content induced by Oxa. CMN and QR ameliorated altered nonenzymatic and enzymatic antioxidants and complex enzymes of mitochondria. We conclude that CMN and QR, by attenuating oxidative stress as evident by mitochondrial dysfunction, hold promise as agents that can potentially reduce Oxa-induced adverse effects in the brain. [ABSTRACT FROM AUTHOR] more...
- Published
- 2016
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36. Evaluation by blue native polyacrylamide electrophoresis colorimetric staining of the effects of physical exercise on the activities of mitochondrial complexes in rat muscle
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A.M. Molnar, A.A. Alves, L. Pereira-da-Silva, D.V. Macedo, and F. Dabbeni-Sala
- Subjects
BN-PAGE ,Colorimetric staining ,Exhaustive physical exercise ,Mitochondrial complexes ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Blue native polyacrylamide electrophoresis (BN-PAGE) is a technique developed for the analysis of membrane complexes. Combined with histochemical staining, it permits the analysis and quantification of the activities of mitochondrial oxidative phosphorylation enzymes using whole muscle homogenates, without the need to isolate muscle mitochondria. Mitochondrial complex activities were measured by emerging gels in a solution containing all specific substrates for NADH dehydrogenase and cytochrome c oxidase enzymes (complexes I and IV, respectively) and the colored bands obtained were measured by optique densitometry. The objective of the present study was the application of BN-PAGE colorimetric staining for enzymatic characterization of mitochondrial complexes I and IV in rat muscles with different morphological and biochemical properties. We also investigated these activities at different times after acute exercise of rat soleus muscle. Although having fewer mitochondria than oxidative muscles, white gastrocnemius muscle presented a significantly higher activity (26.7 ± 9.5) in terms of complex I/V ratio compared to the red gastrocnemius (3.8 ± 0.65, P < 0.05) and soleus (9.8 ± 0.9, P < 0.001) muscles. Furthermore, the complex IV/V ratio of white gastrocnemius muscle was always significantly higher when compared to the other muscles. Ninety-five minutes of exhaustive physical exercise induced a decrease in complex I/V and complex IV/V ratios after all resting times (0, 3 and 6 h) compared to control (P < 0.05), probably reflecting the oxidative damage due to increasing free radical production in mitochondria. These results demonstrate the possible and useful application of BN-PAGE-histochemical staining to physical exercise studies. more...
- Published
- 2004
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37. Caffeic Acid Phenethyl Ester Protects Kidney Mitochondria against Ischemia/Reperfusion Induced Injury in an In Vivo Rat Model
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Darius Trumbeckas, Arvydas Strazdauskas, Rasa Baniene, Sonata Trumbeckaite, and Justina Kamarauskaite
- Subjects
0301 basic medicine ,kidney ,Antioxidant ,antioxidant ,Physiology ,medicine.medical_treatment ,mitochondrial complexes ,education ,Clinical Biochemistry ,Ischemia ,Oxidative phosphorylation ,RM1-950 ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,oxidative stress ,Caffeic acid phenethyl ester ,Molecular Biology ,caffeic acid phenethyl ester ,reactive oxygen species ,030102 biochemistry & molecular biology ,Renal ischemia ,biology ,Cytochrome c ,Cell Biology ,medicine.disease ,ischemia/reperfusion ,mitochondria ,030104 developmental biology ,chemistry ,biology.protein ,population characteristics ,Therapeutics. Pharmacology ,Reperfusion injury ,geographic locations ,Oxidative stress - Abstract
To improve ischemia/reperfusion tolerance, a lot of attention has been focused on natural antioxidants. Caffeic acid phenethyl ester (CAPE), an active component of the resinous exudates of the buds and young leaves of Populus nigra L., Baccharis sarothroides A., etc., and of propolis, possesses unique biological activities such as anti-inflammatory, antioxidant, immunomodulating, and cardioprotective effects, among others. There is a lack of studies showing a link between the antioxidant potential of CAPE and the mechanism of protective action of CAPE at the level of mitochondria, which produces the main energy for the basic functions of the cell. In the kidney, ischemia/reperfusion injury contributes to rapid kidney dysfunction and high mortality rates, and the search for biologically active protective compounds remains very actual. Therefore, the aim of this study was to identify the antioxidant potential of CAPE and to investigate whether CAPE can protect rat kidney mitochondria from in vivo kidney ischemia/reperfusion induced injury. We found that CAPE (1) possesses antioxidant activity (the reducing properties of CAPE are more pronounced than its antiradical properties), CAPE effectively reduces cytochrome c, (2) protects glutamate/malate oxidation and Complex I activity, (3) preserves the mitochondrial outer membrane from damage and from the release of cytochrome c, (4) inhibits reactive oxygen species (ROS) generation in the Complex II (SDH) F site, (5) diminishes ischemia/reperfusion-induced LDH release and protects from necrotic cell death, and (6) has no protective effects on succinate oxidation and on Complex II +III activity, but partially protects Complex II (SDH) from ischemia/reperfusion-induced damage. In summary, our study shows that caffeic acid phenethyl ester protects kidney mitochondrial oxidative phosphorylation and decreases ROS generation at Complex II in an in vivo ischemia/reperfusion model, and shows potential as a therapeutic agent for the development of pharmaceutical preparations against oxidative stress-related diseases. more...
- Published
- 2021
38. Mitochondrial oxygen consumption in permeabilized fibers and its link to colour changes in bovine M. semimembranosus muscle
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Phung, V.T., Khatri, M., Liland, K.H., Slinde, E., Sørheim, O., Almøy, T., Saarem, K., and Egelandsdal, B.
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MITOCHONDRIA , *OXYGEN consumption , *REGRESSION analysis , *FIBERS , *MUSCLES , *METMYOGLOBIN , *VACUUM packaging , *REFLECTANCE spectroscopy - Abstract
Abstract: Animal and muscle characteristics were recorded for 41 cattle. The oxygen consumption rate (OCR) of M. semimembranosus was measured between 3.0–6.4h post mortem (PM3-6) and after 3weeks in a vacuum pack at 4°C. Colour change measurements were performed following the 3weeks using reflectance spectra (400–1100nm) and the colour coordinates L*, a* and b*, with the samples being packaged in oxygen permeable film and stored at 4°C for 167h. Significant individual animal differences in OCR at PM3-6 were found for mitochondrial complexes I and II. OCR of complex I declined with increased temperature and time PM, while residual oxygen-consuming side-reactions (ROX) did not. OCR of stored muscles was dominated by complex II respiration. A three-way regression between samples, colour variables collected upon air exposure and OCR of 3weeks old fibres revealed a positive relationship between OCR and complex II activity and also between OCR and OCRROX. The presence of complex I and β-oxidation activities increased metmyoglobin formation. [Copyright &y& Elsevier] more...
- Published
- 2013
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39. Mitochondrial nutrients stimulate performance and mitochondrial biogenesis in exhaustively exercised rats.
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Sun, M., Qian, F., Shen, W., Tian, C., Hao, J., Sun, L., and Liu, J.
- Subjects
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SKELETAL muscle injuries , *DNA analysis , *REACTIVE oxygen species , *ANALYSIS of variance , *ANIMAL experimentation , *ANTIOXIDANTS , *APOPTOSIS , *ASPARTATE aminotransferase , *CREATINE kinase , *DIETARY supplements , *FISHER exact test , *IMMUNOBLOTTING , *LACTATE dehydrogenase , *LIPID peroxidation (Biology) , *MITOCHONDRIA , *POLYMERASE chain reaction , *PROBABILITY theory , *RATS , *RESEARCH funding , *STATISTICS , *DATA analysis , *OXIDATIVE stress , *ALANINE aminotransferase , *BODY movement , *EXERCISE intensity , *SKELETAL muscle - Abstract
The aim of this study was to investigate the effects of a combination of nutrients on physical performance, oxidative stress and mitochondrial biogenesis in rats subjected to exhaustive exercise. Rats were divided into sedentary control (SC), exhaustive exercise (EC) and exhaustive exercise with nutrient supplementation (EN). The nutrients include (mg/kg/day): R-α-lipoic acid 50, acetyl- l-carnitine 100, biotin 0.1, nicotinamide 15, riboflavin 6, pyridoxine 6, creatine 50, CoQ10 5, resveratrol 5 and taurine 100. Examination of running distances over the 4-week period revealed that EN rats ran significantly longer throughout the entire duration of the exhaustive exercise period compared with the EC rats. Nutrient supplementation significantly inhibited the increase in activities of alanine transaminase, lactate dehydrogenase and creatine kinase, reversed increases in malondialdehyde, inhibited decreases in glutathione S-transferase and total antioxidant capacity in plasma, and suppressed the elevation of reactive oxygen species and apoptosis in splenic lymphocytes. Nutrient supplementation increased the protein expression of mitochondrial complexes I, II and III, mtDNA number and transcription factors involved in mitochondrial biogenesis and fusion in skeletal muscle. These findings suggest that mitochondrial nutrient supplementation can reduce exhaustive exercise-induced oxidative damage and mitochondrial dysfunction, thus leading to enhancement of physical performance and of fatigue recovery. [ABSTRACT FROM AUTHOR] more...
- Published
- 2012
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40. Curcumin Attenuates Aluminum-Induced Oxidative Stress and Mitochondrial Dysfunction in Rat Brain.
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Sood, Pooja, Nahar, Uma, and Nehru, Bimla
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- *
TURMERIC , *OXIDATIVE stress , *MITOCHONDRIAL pathology , *ALZHEIMER'S disease , *PHYSIOLOGICAL effects of aluminum , *PHOSPHORYLATION , *ANTIOXIDANTS , *DRUG administration , *NEUROPHYSIOLOGY - Abstract
Aluminum is neurotoxic both in animals and human beings primarily because of its interference with biological enzymes in key mechanisms of metabolic pathways. Mitochondrial dysfunction is one such mechanism that has been implicated in the pathogenesis of neurodegenerative diseases like Alzheimer's disease. Aluminum toxicity is very closely related to Alzheimer's disease. We evaluated the potentials of curcumin, a known cytoprotectant, against neurotoxic consequences of aluminum that acts through a wide range of mechanisms. Curcumin has been reported to be an antioxidant, and it is this property that is widely held to be responsible for its protective effects in tissue. Aluminum was administered by oral gavage at a dose level of 100 mg/kg body wt/day for a period of 8 weeks. Curcumin was administered in conjunction with aluminum at a dose of 50 mg/kg of body wt i.p. for a period of 8 weeks on alternate days. The effects of different treatments were studied on oxidative phosphorylation and reduced glutathione of different regions of rat brain. The study indicates reduced activity of NADH dehydrogenase (complex I), succinic dehydrogenase (complex II), and cytochrome oxidize (Complex IV) in all the three regions of rat brain, i.e., cerebral cortex, mid brain, and cerebellum. Curcumin supplementation to aluminum-treated rats was able to normalize significantly the activities of all the three mitochondrial complexes as well as reduced glutathione content in all the three regions of brain which were altered following aluminum treatment. We conclude that curcumin, by attenuating oxidative stress, as evident by hypoxia in histological observations and mitochondrial dysfunction holds a promise as an agent that can potentially reduce aluminum-induced adverse effects in brain. [ABSTRACT FROM AUTHOR] more...
- Published
- 2011
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41. Up-regulation of key microRNAs, and inverse down-regulation of their predicted oxidative phosphorylation target genes, during aging in mouse brain
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Li, Na, Bates, David J., An, Jin, Terry, Derek A., and Wang, Eugenia
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- *
PHOSPHORYLATION , *AGING , *ADENOSINE triphosphatase , *PROTEOMICS , *LONGEVITY , *LABORATORY mice - Abstract
Abstract: Although significant advances have been made in the study of the molecular mechanisms controlling brain aging, post-transcriptional gene regulation in normal brain aging has yet to be explored. Our lab recently reported that predominant microRNA up-regulation is observed in liver during aging, with key microRNAs predicted to target detoxification genes. Here we examine the role of microRNA regulation in brain during the normal aging process. MicroRNA microarrays and global proteomic profiling were used to compare the brain tissues of 10-, 18-, 24-, and 33-month-old mice. Our results suggest that: (1) like liver, during aging the brain exhibits predominant microRNA up-regulation, and this trend starts in mid-life; (2) of the 70 up-regulated microRNAs, 27 are predicted to target 10 genes of mitochondrial complexes III, IV, and F0F1-ATPase, which exhibit inversely correlated expression; (3) mice of extreme longevity (33-month old) exhibit fewer microRNA expression changes from 10-month-old levels than do old adult mice (24-month old). We found unique de-regulated microRNAs shared between aging brain and aging liver, as well as brain- vs. liver-specific microRNAs during normal aging. [Copyright &y& Elsevier] more...
- Published
- 2011
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42. Proteomics unravels the exportability of mitochondrial respiratory chains.
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Panfoli, Isabella `, Ravera, Silvia, Bruschi, Maurizio, Candiano, Giovanni, and Morelli, Alessandro
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- 2011
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43. Folic Acid Plus α-Tocopherol Mitigates Amyloid-β-Induced Neurotoxicity through Modulation of Mitochondrial Complexes Activity.
- Author
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Figueiredo, Cláudia P., Bicca, Maíra A., Latini, Alexandra, Prediger, Rui Daniel S., Medeiros, Rodrigo, and Calixto, João B.
- Subjects
- *
FOLIC acid , *VITAMIN E , *AMYLOID beta-protein , *MITOCHONDRIA , *ALZHEIMER'S disease - Abstract
Early symptoms of Alzheimer's disease (AD) have been attributed to amyloid-β (Aβ) toxicity. The pathophysiology of AD is complex and involves several different biochemical pathways, including defective Aβ protein metabolism, neuroinflammation, oxidative processes, and mitochondrial dysfunction. In the current study, we assessed the molecular mechanisms, mainly the modifications in the activity of mitochondrial complexes, whereby the association of folic acid and α-tocopherol protects mice against the Aβ-induced neurotoxicity. Oral treatment with folic acid (50 mg/kg) plus α-tocopherol (500 mg/kg), once a day during 14 consecutive days, protected mice against the Aβ1-40-induced cognitive decline, synaptic loss, and neuronal death. However, chronic treatment comprising folic acid plus α-tocopherol was ineffective on Aβ-induced glial cell activation, suggesting that the effect of this treatment is independent of anti-inflammatory features. Interestingly, the results obtained in our study suggest that mitochondrial energy metabolism is impaired by the Aβ peptide, and upregulation of mitochondrial genes may be a compensatory response, as demonstrated by the increase in mitochondrial complexes I, II, and IV activity, in the hippocampus of mice, after Aβ1-40 injection. Of note, the chronic treatment comprising folic acid plus α-tocopherol prevented the increase in the activity of mitochondrial complexes I and IV induced by Aβ1-40. Together, these results show the antioxidant effect of the combination of folic acid and α-tocopherol, as observed by the decrease in NO generation from iNOS and nNOS, preventing an increase in the activity of mitochondrial complexes, mainly I and IV, and the neuronal death induced by the Aβ1-40 peptide. [ABSTRACT FROM AUTHOR] more...
- Published
- 2011
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44. The Effects of Antidepressants on Mitochondrial Function in a Model Cell System and Isolated Mitochondria.
- Author
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Abdel-Razaq, W., Kendall, D., and Bates, T.
- Subjects
- *
DRUG side effects , *ANTIDEPRESSANTS , *MITOCHONDRIAL pathology , *APOPTOSIS , *CELL death , *GENETIC transcription , *CELL lines - Abstract
The in vitro effects of antidepressant drugs on mitochondrial function were investigated in a CHOβSPAP cell line used previously to determine the effects of antidepressants on gene transcription (Abdel-Razaq et al., Biochem Pharmacol 73:1995-2003, ) and in rat heart isolated mitochondria. Apoptotic effects of clomipramine (CLOM), desipramine (DMI) and of norfluoxetine (NORF, the active metabolite of fluoxetine), on cellular viability were indicated by morphological changes and concentration-dependent increases in caspase-3 activity in CHO cells after 18 h exposure to CLOM, DMI and NORF. However, tianeptine (TIAN) was without effect. CLOM and NORF both reduced integrated mitochondrial function as shown by marked reductions in membrane potential (MMP) in mitochondria isolated from rat hearts. DMI also showed a similar but smaller effect, whereas, TIAN did not elicit any significant change in MMP. Moreover, micromolar concentrations of CLOM, DMI and NORF caused significant inhibitions of the activities of mitochondrial complexes (I, II/III and IV). The inhibitory effects on complex IV activity were most marked. TIAN inhibited only complex I activity at concentrations in excess of 20 μM. The observed inhibitory effects of antidepressants on the mitochondrial complexes were accompanied by a significant decrease in the mitochondrial state-3 respiration at concentrations above 10 μM. The results demonstrate that the apoptotic cell death observed in antidepressant-treated cells could be due to disruption of mitochondrial function resulting from multiple inhibition of mitochondrial enzyme complexes. The possibility that antimitochondrial actions of antidepressants could provide a potentially protective pre-conditioning effect is discussed. [ABSTRACT FROM AUTHOR] more...
- Published
- 2011
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45. DJ-1-deficient mice show less TH-positive neurons in the ventral tegmental area and exhibit non-motoric behavioural impairments.
- Author
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Pham, T. T., Giesert, F., Röthig, A., Floss, T., Kallnik, M., Weindl, K., Hölter, S. M., Ahting, U., Prokisch, H., Becker, L., Klopstock, T., De Angelis, M. Hrabé, Beyer, K., Görner, K., Kahle, P. J., Weisenhorn, D. M. Vogt, and Wurst, W. more...
- Subjects
- *
PARKINSON'S disease , *LABORATORY mice , *PHENOTYPES , *OXIDATIVE stress , *PHOSPHORYLATION - Abstract
Loss of function of DJ-1 (PARK7) is associated with autosomal recessive early-onset Parkinson's disease (PD), one of the major age-related neurological diseases. In this study, we extended former studies on DJ-1 knockout mice by identifying subtle morphological and behavioural phenotypes. The DJ-1 gene trap-induced null mutants exhibit less dopamine-producing neurons in the ventral tegmental area (VTA). They also exhibit slight changes in behaviour, i.e. diminished rearing behaviour and impairments in object recognition. Furthermore, we detected subtle phenotypes, which suggest that these animals compensate for the loss of DJ-1. First, we found a significant upregulation of mitochondrial respiratory enzyme activities, a mechanism known to protect against oxidative stress. Second, a close to significant increase in c-Jun N-terminal kinase 1 phosphorylation in old DJ-1-deficient mice hints at a differential activation of neuronal cell survival pathways. Third, as no change in the density of tyrosine hydroxylase (TH)-positive terminals in the striatum was observed, the remaining dopamine-producing neurons likely compensate by increasing axonal sprouting. In summary, the present data suggest that DJ-1 is implicated in major non-motor symptoms of PD appearing in the early phases of the disease—such as subtle impairments in motivated behaviour and cognition—and that under basal conditions the loss of DJ-1 is compensated [ABSTRACT FROM AUTHOR] more...
- Published
- 2010
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46. Thermal sensitivity of cardiac mitochondrial metabolism in an ectothermic species from a cold environment, Atlantic wolffish (Anarhichas lupus)
- Author
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Lemieux, Hélène, Tardif, Jean-Claude, Dutil, Jean-Denis, and Blier, Pierre U.
- Subjects
- *
WOLFFISHES , *PHYSIOLOGICAL effects of cold temperatures , *MITOCHONDRIA , *COLD-blooded animals , *HEART metabolism , *PHOSPHORYLATION , *TRICARBOXYLIC acids , *DEHYDROGENASES , *SERUM albumin , *SENSITIVITY analysis - Abstract
Abstract: To produce energy, mitochondria use oxidative phosphorylation, a multistep process involving several integrated reactions influenced by temperature. In order to identify which step in the process was most sensitive to temperature in a cold-temperate ectothermic species, we measured the thermal sensitivity of mitochondrial oxidative phosphorylation, as well as the thermal sensitivity of each individual step in this process, in mitochondria isolated from the heart of Atlantic wolffish (Anarhichas lupus). The thermal sensitivity of oxidative phosphorylation (coupled, ADP-stimulated), measured in the presence of pyruvate and malate as substrates, and those of Complexes II and IV activities were the same over the whole range of assay temperatures (5 to 35°C). In contrast, the thermal sensitivity of Complexes I and III, ATPase, pyruvate dehydrogenase and citrate synthase could not be correlated with the thermal sensitivity of oxidative phosphorylation. The first step in the process of oxidative phosphorylation to be negatively affected by increased temperature was shown to be Complex III, followed by the Complex I. This occurred at temperatures above the tolerance limit and well above the range of temperatures occupied by the species. Our results identify specific steps within the electron transport system as potential control point limiting the capacity of Atlantic wolffish cardiac mitochondrial metabolism in response to changes in temperature. [Copyright &y& Elsevier] more...
- Published
- 2010
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47. Thermal sensitivity of oxidative phosphorylation in rat heart mitochondria: Does pyruvate dehydrogenase dictate the response to temperature?
- Author
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Lemieux, Hélène, Tardif, Jean-Claude, and Blier, Pierre U.
- Subjects
- *
PHOSPHORYLATION , *MITOCHONDRIA , *PYRUVATES , *DEHYDROGENASES , *LABORATORY rats , *TEMPERATURE effect , *ELECTRON transport , *LOW temperatures - Abstract
Abstract: To identify the most temperature-sensitive steps in the energy production pathways, we measured the thermal sensitivity of mitochondrial oxidative phosphorylation (OXPHOS), as well as that of the individual steps in this process in rat heart mitochondria. OXPHOS measured in the presence of pyruvate+malate as substrates have an unusually high thermal sensitivity between 5 and 15°C. Furthermore, the thermal sensitivity of OXPHOS correlates with the thermal sensitivity of pyruvate dehydrogenase between 5 and 35°C. Pyruvate dehydrogenase is a potential control point for pyruvate-supported mitochondrial respiration below physiological temperature in rat heart. [Copyright &y& Elsevier] more...
- Published
- 2010
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- View/download PDF
48. Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice.
- Author
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Rhein, Virginie, Xiaomin Song, Wiesner, Andreas, Ittner, Lars M., Baysang, Ginette, Meier, Fides, Ozmen, Laurence, Bluethmann, Horst, Drösee, Stefan, Brandt, Ulrich, Savaskan, Egemen, Czech, Christian, Götz, Jürgen, and Eckert, Anne more...
- Subjects
- *
ALZHEIMER'S disease , *NEURONS , *SYNAPSES , *AMYLOID beta-protein , *ELECTRON transport , *ENERGY metabolism , *LABORATORY mice , *MASS spectrometry - Abstract
Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ)-containing plaques, neurofibrillary tangles, and neuron and synapse loss. Tangle formation has been reproduced in P301L tau transgenic pR5 mice, whereas APPswPS2N141I double-transgenic APP152 mice develop Aβ plaques. Cross-breeding generates triple transgenic (tripleAD) mice that combine both pathologies in one model. To determine functional consequences of the combined Aβ and tau pathologies, we performed a proteomic analysis followed by functional validation. Specifically, we obtained vesicular preparations from tripleAD mice, the parental strains, and nontransgenic mice, followed by the quantitative mass-tag labeling proteomic technique iTRAQ and mass spectrometry. Within 1,275 quantified proteins, we found a massive deregulation of 24 proteins, of which one-third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Notably, deregulation of complex I was tau dependent, whereas deregulation of complex IV was Aβ dependent, both at the protein and activity levels. Synergistic effects of Aβ and tau were evident in 8-month-old tripleAD mice as only they showed a reduction of the mitochondrial membrane potential at this early age. At the age of 12 months, the strongest defects on OXPHOS, synthesis of ATP, and reactive oxygen species were exhibited in the tripleAD mice, again emphasizing synergistic, age-associated effects of Aβ and tau in perishing mitochondria. Our study establishes a molecular link between Aβ and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics. [ABSTRACT FROM AUTHOR] more...
- Published
- 2009
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49. Synaptic ribbon plasticity, ribbon size and potential regulatory mechanisms in utricular and saccular maculae.
- Author
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Ross, Muriel D. and Varelas, Joseph
- Subjects
- *
SYNAPSES , *NERVE endings , *NEUROPLASTICITY , *MITOCHONDRIA , *HAIR cells , *RATS - Abstract
The mean number of synaptic ribbons in type II hair cells of the rat utricular macula increased significantly in weightlessness. In contrast, ribbon synapses of saccular type I hair cells displayed a significant decline early inflight and postflight, and a late numerical overshoot. Further study indicated that the saccular macula had less ultrastructural complexly than the utricular. Additionally, synaptic ribbons were statistically larger in type II hair cells of both maculae, apparently a locus-related scaling effect. A major new finding is that mitochondria in calyces and collateral terminals were linked to vesicles, tubules of smooth endoplasmic reticulum and cell membranes by filaments, forming mitochondrial complexes (MCs). MCs predominated basally in the calyx where calyceal/type I hair cell borders were bound by filaments; at calyceal invaginations of type I hair cells; in calyces and collaterals near synaptic ribbon sites; and in collaterals near reciprocal synapses. MCs may participate in feedback mechanisms at these locations to help regulate synaptic ribbon activity and plasticity in altered gravitational environments. [ABSTRACT FROM AUTHOR] more...
- Published
- 2005
- Full Text
- View/download PDF
50. Cadmium-Induced Cytotoxicity: Effects on Mitochondrial Electron Transport Chain
- Author
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Claudia Fiorillo, Niccolò Taddei, Matteo Becatti, Massimo Gulisano, Alessandra Pacini, and Jacopo Junio Valerio Branca
- Subjects
Pollutant ,Cadmium ,cadmium ,Mini Review ,mitochondrial complexes ,chemistry.chemical_element ,cadmium, cytotoxicity, mitochondria, mitochondrial electron transport chain, mitochondrial complexes ,Cell Biology ,Mitochondrion ,Electron transport chain ,Cell biology ,mitochondria ,Cell and Developmental Biology ,mitochondrial electron transport chain ,chemistry.chemical_compound ,lcsh:Biology (General) ,chemistry ,Toxicity ,cytotoxicity ,Cytotoxicity ,lcsh:QH301-705.5 ,Intracellular ,Developmental Biology ,Toxicant - Abstract
Cadmium (Cd) is a well-known heavy metal and environmental toxicant and pollutant worldwide, being largely present in every kind of item such as plastic (toys), battery, paints, ceramics, contaminated water, air, soil, food, fertilizers, and cigarette smoke. Nowadays, it represents an important research area for the scientific community mainly for its effects on public health. Due to a half-life ranging between 15 and 30 years, Cd owns the ability to accumulate in organs and tissues, exerting deleterious effects. Thus, even at low doses, a Cd prolonged exposure may cause a multiorgan toxicity. Mitochondria are key intracellular targets for Cd-induced cytotoxicity, but the underlying mechanisms are not fully elucidated. The present review is aimed to clarify the effects of Cd on mitochondria and, particularly, on the mitochondrial electron transport chain. more...
- Published
- 2020
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