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Glioma is a refractory malignant tumor with a powerful capacity for invasiveness and a poor prognosis. This study aims to investigate the role and mechanism of tubulin beta class IVA (TUBB4A) in glioma progression. The differential expression of TUBB4A in humans was obtained from databases and analyzed. Glioma cells U251-MG and U87-MG were intervened by pcDNA3.1(+) and TUBB4A overexpression plasmid. MTT, CCK8, LDH, wound healing, transwell, and western blotting were used to explore whether TUBB4A participates in the development of glioma. Reactive oxygen species (ROS) were detected by the DCFH-DA probe. Mitochondrial membrane potential (MMP) was examined by JC-1. It was found that TUBB4A expression level correlated with tumor grade, IDH1 status, 1p/19q status, and poor survival in glioma patients. In addition, TUBB4A overexpression inhibited the proliferation, migration, and invasion of U251-MG and U87-MG, while increasing the degree of apoptosis. Notably, TUBB4A overexpression promotes ROS generation and MMP depolarization, and induces mitophagy through the PINK1/Parkin pathway. Interestingly, mitochondria-targeted ROS scavenger reversed the effect of TUBB4A overexpression on PINK1/Parkin expression and mitophagy, whereas mitophagy inhibitor did not affect ROS production. And the effect of TUBB4A overexpression on mitophagy and glioma progression was consistent with that of PINK1/Parkin agonist. In conclusion, TUBB4A is a molecular marker for predicting the prognosis of glioma patients and an effective target for inhibiting glioma progression by regulating ROS-PINK1/Parkin-mitophagy pathway. [ABSTRACT FROM AUTHOR]

High‐producing dairy cows are susceptible to altered redox balance owing to their high secretion and strong metabolism during transition to lactation. Previously reports demonstrated that pterostilbene (PTE) alleviate hydrogen peroxide (H2O2)-induced oxidative damage. However, molecular mechanism underlying protective role of PTE in H2O2-elicited oxidative stress in bovine mammary epithelial cells (MAC-T cells) remains unclear. The aims of our research is to clarify the potential molecular mechanisms of PTE in H2O2-triggered oxidative damage. MAC-T cells were pre-treated with PTE (0, 10, 25 and 50 μM) for 12 h and then cultured with H2O2 (0, 100, 200, 400, 600, 800 and 1000 μM) for another 24 h. The results were interpreted by CCK8, western blot, and immunofluorescence assay. Results showed that PTE significantly attenuated H2O2-mediated reduction in T-AOC, SOD and GSH-Px activity. Mechanistic studies found that PTE restricted the H2O2-induced protein expression of HO-1, GPX4 and SOD1, and PTE reversed intracellular MDA and ROS generation and decreased the MMP in MAC-T cells. Moreover, H2O2 exposure markedly inhibited mitophagy, whereas PTE pre-treatment activated PINK1/Parkin-mediated mitophagy pathway, which further limited ROS production. Overall, PTE can be used to improve oxidative stress and as a novel antioxidant agent in dairy cows. Highlights PTE restored the levels of H2O2-induced oxidative stress markers (T-AOC, SOD, GSH-Px and MDA) in MAC-T cells. PTE effectively blocked the increase of protein expression (HO-1, SOD1 and GPX4) in H2O2-induced MAC-T cells. PTE remarkably decreased the accumulation of ROS and improved MMP in H2O2-induced MAC-T cells. PTE exerted a significant protective effect against oxidative stress injury by reducing the inhibition of H2O2 on mitophagy.

The maintenance of healthy mitochondria is essential for neuronal survival and relies upon mitochondrial quality control pathways involved in mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy (mitophagy). Mitochondrial dysfunction is critically implicated in Parkinson's disease (PD), a brain disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Consequently, impaired mitochondrial quality control may play a key role in PD pathology. This is affirmed by work indicating that genes such as PRKN and PINK1, which participate in multiple mitochondrial processes, harbor PD-associated mutations. Furthermore, mitochondrial complex-I-inhibiting toxins like MPTP and rotenone are known to cause Parkinson-like symptoms. At the heart of PD is alpha-synuclein (αS), a small synaptic protein that misfolds and aggregates to form the disease's hallmark Lewy bodies. The specific mechanisms through which aggregated αS exerts its neurotoxicity are still unknown; however, given the vital role of both αS and mitochondria to PD, an understanding of how αS influences mitochondrial maintenance may be essential to elucidating PD pathogenesis and discovering future therapeutic targets. Here, the current knowledge of the relationship between αS and mitochondrial quality control pathways in PD is reviewed, highlighting recent findings regarding αS effects on mitochondrial biogenesis, dynamics, and autophagy. [ABSTRACT FROM AUTHOR]

High‐producing dairy cows are susceptible to altered redox balance owing to their high secretion and strong metabolism during transition to lactation. Previously reports demonstrated that pterostilbene (PTE) alleviate hydrogen peroxide (H2O2)-induced oxidative damage. However, molecular mechanism underlying protective role of PTE in H2O2-elicited oxidative stress in bovine mammary epithelial cells (MAC-T cells) remains unclear. The aims of our research is to clarify the potential molecular mechanisms of PTE in H2O2-triggered oxidative damage. MAC-T cells were pre-treated with PTE (0, 10, 25 and 50 μM) for 12 h and then cultured with H2O2 (0, 100, 200, 400, 600, 800 and 1000 μM) for another 24 h. The results were interpreted by CCK8, western blot, and immunofluorescence assay. Results showed that PTE significantly attenuated H2O2-mediated reduction in T-AOC, SOD and GSH-Px activity. Mechanistic studies found that PTE restricted the H2O2-induced protein expression of HO-1, GPX4 and SOD1, and PTE reversed intracellular MDA and ROS generation and decreased the MMP in MAC-T cells. Moreover, H2O2 exposure markedly inhibited mitophagy, whereas PTE pre-treatment activated PINK1/Parkin-mediated mitophagy pathway, which further limited ROS production. Overall, PTE can be used to improve oxidative stress and as a novel antioxidant agent in dairy cows. Highlights: PTE restored the levels of H2O2-induced oxidative stress markers (T-AOC, SOD, GSH-Px and MDA) in MAC-T cells. PTE effectively blocked the increase of protein expression (HO-1, SOD1 and GPX4) in H2O2-induced MAC-T cells. PTE remarkably decreased the accumulation of ROS and improved MMP in H2O2-induced MAC-T cells. PTE exerted a significant protective effect against oxidative stress injury by reducing the inhibition of H2O2 on mitophagy. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Early treatment of mandibular advancement device (MAD) reverses the abnormal changes resulting from obstructive sleep apnoea (OSA), but the underlying mechanism is not clear. We analysed the changes of genioglossus function before and after MAD treatment in OSA rabbits and explored the mechanism of mitochondrial autophagy.Eighteen male New Zealand rabbits were randomised into three groups: the control group, Group OSA, and Group MAD. After successful modelling, all animals were induced sleep in supine positions for 4–6 h per day for 8 weeks. Cone beam computed tomography (CBCT) and polysomnography (PSG) were performed to record sleep conditions. The genioglossus contractile force and the levels of LC3‐I, LC3‐II, Beclin‐1, PINK1 and Parkin were detected in three groups. In vitro, C2C12 myoblast cells were cultured under normoxic or hypoxic conditions for 24 h, and then the changes in mitochondrial structure and accumulation of autolysosomes were detected by transmission electron microscopy (TEM).The contractile tension of the genioglossus in Group OSA was significantly lower than that in the control group. The ratio of LC3II/LC3I and the levels of Beclin‐1, PINK1 and Parkin were higher in Group OSA than that in the control group. And the abnormal changes were tended to be normal after MAD treatment. The mitochondrial structure was disrupted, and the number of autolysosomes increased in C2C12 after 24 h of hypoxia.MAD treatment in male rabbits may decrease the contractile tension of the genioglossus and increase the level of mitochondrial autophagy caused by OSA. And the mechanism of mitochondrial autophagy was mediated by the PINK1/Parkin pathway in male rabbits. [ABSTRACT FROM AUTHOR]

Hong Ding,1 Xiaofan Lu,2 Huimin Wang,3 Wenming Chen,3 Bing Niu4 1Otolaryngology Department, The Second Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 2Respiratory Department, The Second Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 3Otolaryngology Department, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 4Stomatology Department, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Hong Ding; Bing Niu, Henan University of Chinese Medicine, The Second Clinical Medical College, 6 Dongfeng Road, Jinshui District, Zhengzhou City, Henan Province, 450002, People’s Republic of China, Email superding@hactcm.edu.cn; 13838061768@163.comPurpose: Accumulating evidence indicates that oxidative stress and inflammation are the pathological basis of allergic diseases. Inhibition of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome could ameliorate allergic rhinitis (AR). Here, we explored the effects and mechanisms that underlie NLRP3 inhibition on oxidative stress and inflammation in AR.Methods: Ovalbumin (OVA)-induced AR murine model was established using wild-type (WT) and NLRP3-deficient mice. HNEpCs were stimulated with interleukin (IL)-13 with MCC950 pretreatment or PTEN-induced putative kinase 1 (PINK1) siRNA. The indicators of oxidative stress, inflammation, apoptosis, and mitophagy were determined both in vivo and in vitro.Results: NLRP3 knockout (KO) reduced the frequency of nasal rubbing and sneezing, the infiltration of eosinophils, the number of mast cells, and the accumulation of goblet cells in AR mice after OVA stimulation. The NLRP3 KO AR mice exhibited the increased concentrations of OVA-specific immunoglobulin E (OVA-sIgE), IL-1β, IL-4, IL-13, IL-6, TNF-α, and the upregulated level of IFN-γ. NLRP3 KO significantly inhibited oxidative stress, and also markedly decreased apoptosis in the nasal mucosa of AR mice. Moreover, evaluated protein expressions of PINK1, enzyme 3 (E3) ubiquitin ligase PRKN (Parkin), and LC3 II, decreased expression of TOM20, as well as the increased colocalization of LC3 with mitochondria were observed in NLRP3 KO AR mice. In vitro, IL-13 exposure increased the levels of NLRP3 and IL-1β. Inhibition of NLRP3 using MCC950 enhanced PINK1/Parkin-mediated mitophagy but attenuated inflammation, oxidative stress, and apoptosis. However, PINK1 knockdown abrogated mitophagy and also reversed the protective effects of MCC950 on inflammation, oxidative stress, and apoptosis in HNEpCs stimulated with IL-13.Conclusion: Inhibition of NLRP3 inflammasome exerts the protective effects on AR by facilitating mitophagy regulated by PINK1/Parkin signaling pathway.Keywords: NLRP3, mitophagy, inflammation, oxidative stress, PINK1/Parkin

Abstract Reproductive aging not only affects the fertility and physical and mental health of women but also accelerates the aging process of other organs. There is an urgent need newfor novel mechanisms, targets, and drugs to break the vicious cycle of mitochondrial dysfunction, redox imbalance, and germ cell apoptosis associated with ovarian aging. Autophagy, recognized as a longevity mechanism, has recently become a focal point in anti-aging research. Although mitophagy is a type of autophagy, its role and regulatory mechanisms in ovarian aging, particularly in age-related ovarian function decline, remain unclear. Nerve growth factor inducible gene B (Nur77) is an early response gene that can be stimulated by oxidative stress, DNA damage, metabolism, and inflammation. Recent evidence recommends that decreased expression of Nur77 is associated with age-related myocardial fibrosis, renal dysfunction, and Parkinson's disease; however, its association with ovarian aging has not been studied yet. We herein identified Nur77 as a regulator of germ cell senescence, apoptosis, and mitophagy and found that overexpression of Nur77 can activate mitophagy, improve oxidative stress, reduce apoptosis, and ultimately enhance ovarian reserve in aged mice ovaries. Furthermore, we discovered an association between Nur77 and the AKT pathway through String and molecular docking analyses. Experimental confirmation revealed that the AKT/mTOR signaling pathway is involved in the regulation of Nur77 in ovarian function. In conclusion, our results suggest Nur77 as a promising target for preventing and treating ovarian function decline related to reproductive aging.

Aflatoxin B1 (AFB1) is extremely harmful to both humans and animals. Mitophagy is a selective process of self‐elimination and has an important role in controlling mitochondrial quality. The present study aimed to investigate the effect of reactive oxygen species (ROS) accumulation on AFB1‐induced mitophagy in HepG2 cells to provide a new perspective from which to design novel therapeutic strategies to treat AFB1 poisoning. ROS release was induced in HepG2 cells with AFB1 (10 μmol/L). Cell autophagy activity, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) levels, Parkin translocation and both the transcription and expression of mitophagy‐related proteins were measured when N‐acetyl‐L‐cysteine (NAC) partially decreased the ROS level, while the knockdown of nuclear factor erythroid 2‐related factor 2 (Nrf2) resulted in a large accumulation of ROS. The results reveal that NAC pretreatment ameliorated the decline in both the MMP and the ATP levels while also activating phosphoglycerate mutase 5 (PGAM5)‐PTEN‐induced kinase 1 (PINK1)/Parkin, while the Nrf2 knockdown group exhibited the opposite trend. These results suggest that AFB1‐induced mitophagy in HepG2 cells depends on ROS, and proper ROS activates mitophagy to play a protective role. [ABSTRACT FROM AUTHOR]

Reproductive aging not only affects the fertility and physical and mental health of women but also accelerates the aging process of other organs. There is an urgent need newfor novel mechanisms, targets, and drugs to break the vicious cycle of mitochondrial dysfunction, redox imbalance, and germ cell apoptosis associated with ovarian aging. Autophagy, recognized as a longevity mechanism, has recently become a focal point in anti-aging research. Although mitophagy is a type of autophagy, its role and regulatory mechanisms in ovarian aging, particularly in age-related ovarian function decline, remain unclear. Nerve growth factor inducible gene B (Nur77) is an early response gene that can be stimulated by oxidative stress, DNA damage, metabolism, and inflammation. Recent evidence recommends that decreased expression of Nur77 is associated with age-related myocardial fibrosis, renal dysfunction, and Parkinson's disease; however, its association with ovarian aging has not been studied yet. We herein identified Nur77 as a regulator of germ cell senescence, apoptosis, and mitophagy and found that overexpression of Nur77 can activate mitophagy, improve oxidative stress, reduce apoptosis, and ultimately enhance ovarian reserve in aged mice ovaries. Furthermore, we discovered an association between Nur77 and the AKT pathway through String and molecular docking analyses. Experimental confirmation revealed that the AKT/mTOR signaling pathway is involved in the regulation of Nur77 in ovarian function. In conclusion, our results suggest Nur77 as a promising target for preventing and treating ovarian function decline related to reproductive aging. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to further elucidate the mechanism of ginsenoside Rg1 in the treatment of cerebral ischemia-reperfusion. Methods: In this study, we observed the apoptosis of RM cells (microglia) after oxygen-glucose deprivation/reoxygenation (OGD/R) modeling before and after Rg1 administration, changes in mitochondrial membrane potential, changes in the content of Reactive oxygen species (ROS) and inflammatory vesicles NLR Family Pyrin Domain Containing 3 (NLRP3), and the expression levels of autophagy-related proteins, inflammatory factors, and apoptosis proteins. We further examined the pathomorphological changes in brain tissue, neuronal damage, changes in mitochondrial morphology and mitochondrial structure, and the autophagy-related proteins, inflammatory factors, and apoptosis proteins expression levels in CI/RI rats before and after administration of Rg1 in vivo experiments. Results: In vitro experiments showed that Rg1 induced mitochondrial autophagy, decreased mitochondrial membrane potential, and reduced ROS content thereby inhibiting NLRP3 activation, decreasing secretion of inflammatory factors and RM cell apoptosis by regulating the PTEN induced putative kinase 1(Pink1) /Parkin signaling pathway. In vivo experiments showed that Rg1 induced mitochondrial autophagy, inhibited NLRP3 activation, improved inflammatory response, and reduced apoptosis by regulating the Pink1/Parkin signaling pathway, and Rg1 significantly reduced the area of cerebral infarcts, improved the pathological state of brain tissue, and attenuated the neuronal damage, thus improving cerebral ischemia/reperfusion injury in rats. Conclusion: Our results suggest that ginsenoside Rg1 can ameliorate cerebral ischemia-reperfusion injury by modulating Pink1/ Parkin-mediated mitochondrial autophagy in microglia and inhibiting microglial NLRP3 activation.

Abstract Colorectal cancer (CRC) is a prevalent global health issue, with 5-fluorouracil (5-FU) being a commonly used chemotherapeutic agent for its treatment. However, the efficacy of 5-FU is often hindered by drug tolerance. Sodium butyrate (NaB), a derivative of intestinal flora, has demonstrated anti-cancer properties both in vitro and in vivo through pro-apoptotic effects and has shown promise in improving outcomes when used in conjunction with traditional chemotherapy agents. This study seeks to evaluate the impact and potential mechanisms of NaB in combination with 5-FU on CRC. We employed a comprehensive set of assays, including CCK-8, EdU staining, Hoechst 33258 staining, flow cytometry, ROS assay, MMP assay, immunofluorescence, and mitophagy assay, to detect the effect of NaB on the biological function of CRC cells in vitro. Western blotting and immunohistochemistry were used to verify the above experimental results. The xenograft tumor model was established to evaluate the in vivo anti-CRC activity of NaB. Subsequently, 16S rRNA gene sequencing was used to analyze the intestinal flora. The findings of our study demonstrate that sodium butyrate (NaB) exerts inhibitory effects on tumor cell proliferation and promotes tumor cell apoptosis in vitro, while also impeding tumor progression in vivo through the enhancement of the mitophagy pathway. Furthermore, the combined treatment of NaB and 5-fluorouracil (5-FU) yielded superior therapeutic outcomes compared to monotherapy with either agent. Moreover, this combination therapy resulted in the specific enrichment of Bacteroides, LigiLactobacillus, butyric acid-producing bacteria, and acetic acid-producing bacteria in the intestinal microbiota. The improvement in the intestinal microbiota contributed to enhanced therapeutic outcomes and reduced the adverse effects of 5-FU. Taken together, these findings indicate that NaB, a histone acetylation inhibitor synthesized through intestinal flora fermentation, has the potential to significantly enhance the therapeutic efficacy of 5-FU in CRC treatment and improve the prognosis of CRC patients.

Abstract Background 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. Methods A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. Results In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. Conclusion OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.

Sepsis is one of major reasons of cardiorenal syndrome type 5 (CRS-5), resulting in irreversible tissue damage and organ dysfunction. Macrophage has been demonstrated to play key role in the pathophysiology of sepsis, highlighting the need to identify therapeutic targets for modulating macrophage phenotype in sepsis. In this study, a rapid-releasing hydrogen sulfide (H2S) donor NaSH, and a slow-releasing H2S compound S-propargyl-cysteine (SPRC) which is derived from garlic, have been studied for the immune-regulatory effects on macrophages. The NaSH and SPRC showed the potential to protect the heart and kidney from tissue injury induced by LPS. The immunohistochemistry of F4/80+ revealed that the infiltration of macrophages in the heart and kidney tissues of LPS-treated mice was reduced by NaSH and SPRC. In addition, in the LPS-triggered inflammatory cascade of RAW264.7 macrophage cells, NaSH and SPRC exhibited significantly inhibitory effects on the secretion of inflammatory cytokines, production of reactive oxygen species (ROS), and regulation of the macrophage phenotype from M1-like to M2-like. Moreover, autophagy, a crucial process involved in the elimination of impaired proteins and organelles during oxidative stress and immune response, was induced by NaSH and SPRC in the presence of LPS stimulation. Consequently, there was an increase in the number of mitochondria and an improvement in mitochondrial membrane potential. This process was mainly mediated by PINK1/Parkin pathway mediated mitophagy. These results demonstrated that the immunoregulatory effects of H2S donors were through the PINK1/Parkin-mediated mitophagy pathway. Overall, our study provided a new therapeutic direction in LPS-induced cardiorenal injury. [ABSTRACT FROM AUTHOR]

Radiation‐induced heart damage caused by low‐dose X‐rays has a significant impact on tumour patients' prognosis, with cardiac hypertrophy being the most severe noncarcinogenic adverse effect. Our previous study demonstrated that mitophagy activation promoted cardiac hypertrophy, but the underlying mechanisms remained unclear. In the present study, PARL‐IN‐1 enhanced excessive hypertrophy of cardiomyocytes and exacerbated mitochondrial damage. Isobaric tags for relative and absolute quantification‐based quantitative proteomics identified NDP52 as a crucial target mediating cardiac hypertrophy induced by low‐dose X‐rays. SUMOylation proteomics revealed that the SUMO E3 ligase MUL1 facilitated NDP52 SUMOylation through SUMO2. Co‐IP coupled with LC–MS/MS identified a critical lysine residue at position 262 of NDP52 as the key site for SUMO2‐mediated SUMOylation of NDP52. The point mutation plasmid NDP52K262R inhibited mitophagy under MUL1 overexpression, as evidenced by inhibition of LC3 interaction with NDP52, PINK1 and LAMP2A. A mitochondrial dissociation study revealed that NDP52K262R inhibited PINK1 targeting to endosomes early endosomal marker (EEA1), late/lysosome endosomal marker (LAMP2A) and recycling endosomal marker (RAB11), and laser confocal microscopy confirmed that NDP52K262R impaired the recruitment of mitochondria to the autophagic pathway through EEA1/RAB11 and ATG3, ATG5, ATG16L1 and STX17, but did not affect mitochondrial delivery to lysosomes via LAMP2A for degradation. In conclusion, our findings suggest that MUL1‐mediated SUMOylation of NDP52 plays a crucial role in regulating mitophagy in the context of low‐dose X‐ray‐induced cardiac hypertrophy. Two hundred sixty‐second lysine of NDP52 is identified as a key SUMOylation site for low‐dose X‐ray promoting mitophagy activation and cardiac hypertrophy. Collectively, this study provides novel implications for the development of therapeutic strategies aimed at preventing the progression of cardiac hypertrophy induced by low‐dose X‐rays. [ABSTRACT FROM AUTHOR]

Background: Paclitaxel (PTX) resistance has become a notable clinical concern of Non‐small cell lung cancer (NSCLC). Our study aim is to investigate the effects of Resveratrol (RES) on NSCLC cells that have developed resistance to PTX. The NSCLC cell line A549 was employed in this investigation to establish a PTX‐resistant NSCLC cell line, denoted as A549/PTX, and established tumor transplantaton model. The presence of miR‐671‐5p, Stomatin‐like protein 2 (STOML2), and mitophagy biomarkers was evaluated using quantitative teal‐time PCR (qRT‐PCR) and western blot, The assessment of cell proliferation and apoptosis was conducted through the utilisation of colony formation and flow cytometry assays. The investigation of mitochondrial autolysosomes was conducted using transmission electron microscopy (TEM). Our results showed that the application of RES therapy resulted in a substantial improvement in the sansitivity of A549/PTX cells. RES exhibited an augmentation of apoptosis and a suppression of mitophagy in A549/PTX cells. RES induced an upregulation in the expression of miR‐671‐5p. This, in turn, leaded to the inhibition of STOML2, a protein that directly interacts with PINK1. In summary, our research indicates that RES improved the susceptibility of A549/PTX cells to PTX through miR‐671‐5p‐mediated STOML2 inhibition. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recent evidence suggests that autophagy, as a cell self-protection mechanism, plays an important role in regulating osteoblast function and maintaining osteoblast homeostasis. It has an important influence on the treatment and prognosis of periprosthetic osteolysis. OBJECTIVE: To provide new therapeutic ideas and potential therapeutic targets for periprosthetic osteolysis by summarizing previous studies on the autophagy mechanism of osteoblasts. METHODS: The first author used the computer to search the articles published from 2015 to 2022. In Chinese, the search terms “wear particles, periprosthetic osteolysis, osteoblasts, signal pathways, autophagy” were used to search the databases of CNKI, WanFang, and VIP. In English, the PubMed and Web of Science databases were retrieved with “wear debris, wear particles, peri*prosthetic osteolysis, PPOL, aseptic loosening, osteoblast, OB, signal path, autophagy”. A total of 98 articles were included according to the inclusion criteria. RESULTS AND CONCLUSION: In periprosthetic osteolysis, the changes in the autophagy ability of osteoblasts induced by wear particles play a key role in the development and outcome of the disease. A variety of signaling pathways jointly mediate autophagy in osteoblasts, among which the key pathways include AMPK/ULK1/mTOR, nuclear factor-κB, Pink1/Parkin, etc. AMPK, mTOR, and ULK1 can regulate each other and jointly maintain the stability of the autophagy level. There is a complex crosstalk between the nuclear factor-κB pathway and autophagy. PINK1 and Parkin are accumulated on the surface of the damaged mitochondrial membrane, inducing autophagy. There is crosstalk among multiple signaling pathways, which form a complex autophagy network under their mutual influence. Moreover, the activation of the same autophagy pathway in different cells may bring about completely opposite effects. Moderate autophagy induced by wear particles can reduce the apoptosis of osteoblasts, enhance their differentiation and mineralization ability, and improve the prognosis of osteolysis around the prosthesis. On the contrary, insufficient or excessive activation of autophagy will cause damage to osteoblasts and promote the progress of osteolysis. Therefore, targeting the level of autophagy of osteoblasts induced by wear particles through drugs or genes may be one of the directions for the treatment of periprosthetic osteolysis. [ABSTRACT FROM AUTHOR]

Prion diseases are a group of neurodegenerative diseases characterized by mitochondrial dysfunction and neuronal death. Mitophagy is a selective form of macroautophagy that clears injured mitochondria. Prohibitin 2 (PHB2) has been identified as a novel inner membrane mitophagy receptor that mediates mitophagy. However, the role of PHB2 in prion diseases remains unclear. In this study, we isolated primary cortical neurons from rats and used the neurotoxic prion peptide PrP106–126 as a cell model for prion diseases. We examined the role of PHB2 in PrP106–126-induced mitophagy using Western blotting and immunofluorescence microscopy and assessed the function of PHB2 in PrP106–126-induced neuronal death using the cell viability assay and the TUNEL assay. The results showed that PrP106–126 induced mitochondrial morphological abnormalities and mitophagy in primary cortical neurons. PHB2 was found to be indispensable for PrP106–126-induced mitophagy and was involved in the accumulation of PINK1 and recruitment of Parkin to mitochondria in primary neurons. Additionally, PHB2 depletion exacerbated neuronal cell death induced by PrP106–126, whereas the overexpression of PHB2 alleviated PrP106–126 neuronal toxicity. Taken together, this study demonstrated that PHB2 is indispensable for PINK1/Parkin-mediated mitophagy in PrP106–126-treated neurons and protects neurons against the neurotoxicity of the prion peptide. [ABSTRACT FROM AUTHOR]

The neurotoxicity of 2,2',4,4'‐tetrabromodiphenyl ether (PBDE‐47) is closely linked to mitochondrial abnormalities while mitophagy is vital for mitochondrial homeostasis. However, whether PBDE‐47 disrupts mitophagy contributing to impaired neurodevelopment remain elusive. Here, this study showed that neonatal PBDE‐47 exposure caused learning and memory deficits in adult rats, accompanied with striatal mitochondrial abnormalities, neuronal apoptosis and the resultant neuronal loss. Mechanistically, PBDE‐47 suppressed PINK1/Parkin‐mediated mitophagy induction and degradation, inducing mitophagosome accumulation and mitochondrial dysfunction in vivo and in vitro. Additionally, stimulation of mitophagy by adenovirus‐mediated Parkin or Autophagy‐related protein 7 (Atg7) overexpression aggravated PBDE‐47‐induced mitophagosome accumulation, mitochondrial dysfunction, neuronal apoptosis and death. Conversely, suppression of mitophagy by the siRNA knockdown of Atg7 rescued PBDE‐47‐induced detrimental consequences. Importantly, melatonin, a hormone secreted rhythmically by the pineal, improved PBDE‐47‐caused neurotoxicity via preventing neuronal apoptosis and loss by restoring mitophagic activity and mitochondrial function. These neuroprotective effects of melatonin depended on activation of the AMP‐activated protein kinase (AMPK)/Unc‐51‐like kinase 1 (ULK1) signaling. Collectively, these data indicate that PBDE‐47 impairs mitophagy to perturb mitochondrial homeostasis, thus triggering apoptosis, leading to neuronal loss and consequent neurobehavioral deficits. Manipulation of the AMPK‐mitophagy axis via melatonin could be a novel therapeutic strategy against developmental PBDE‐47 neurotoxicity. [ABSTRACT FROM AUTHOR]

Objective To study the cffcct of ligustrazine injcction on mitophagy in neonatal rats with hypoxic-ischemic encephalopathy (HIE) and its molecular mechanism. Methods Neonatal Sprague-Dawley rats, aged 7 days, were randomly divided into a sham-operation group with 8 rats, a model group with 12 rats, and a ligustrazine group with 12 rats. The rats in the model group and the ligustrazine group were used to establish a neonatal rat model of HIE by ligation of the left common carotid artery followed by hypoxia treatment, and blood vessels were exposed without any other treatment for the rats in the sham-operation group. The rats in the ligustrazine group were intraperitoneally injected with ligustrazine (20 mg/kg) daily after hypoxia-ischcmia, and those in the sham-operation group and the model group were intraperitoneally injected with an equal volume of normal saline daily. Samples were collected after 7 days of treatment. Hematoxylin and cosin staining and Nissl staining were used to observe the pathological changes of neurons in brain tissue; immunohistochemical staining was used to observe the positive expression of PINK1 and Parkin in the hippocampus and cortex; TUNEL staining was used to measure neuronal apoptosis; Western blotting was used to measure the expression levels of the mitophagy pathway proteins PINK1 and Parkin and the autophagy-related proteins Beclin-1, microtubule-associated protein 1 light chain 3 (LC3), and ubiquitin-binding protein (P62). Results Compared with the sham-operation group, the model group had a significant reduction in the number of neurons, an increase in intercellular space, loose arrangement, lipid vacuolization, and a reduction in Nissl bodies. The increased positive expression of PINK1 and Parkin, apoptosis rate of neurons, and protein expression levels of PINK1, Parkin, Beclin1 and LC3 (P<0.05) and the decreased protein expression level of P62 in the hippocampus were also observed in the model group (P<0.05). Compared with the model group, the ligustrazine group had a significant increase in the number of neurons with ordered arrangement and an increase in Nissl bodies, significant reductions in the positive expression of PINK1 and Parkin, the apoptosis rate of neurons, and the protein expression levels of PINK1, Parkin, Beclin1, and LC3 (P<0.05), and a significant increase in the protein expression level of P62 (P<0.05). Conclusions Ligustrazine can alleviate hypoxic-ischemic brain damage and inhibit neuronal apoptosis in neonatal rats to a certain extent, possibly by inhibiting PINK1/Parkin-mediated autophagy. [ABSTRACT FROM AUTHOR]

Abstract PPARγ agonists have been proven to be neuroprotective in vitro and in vivo models of Alzheimer’s disease (AD). In the present study, we identified ligustrazine piperazine derivative (LPD) as a novel PPARγ agonist, which was detected by a dual-luciferase reporter assay system. LPD treatment dose-dependently reduced Aβ40 and Aβ42 levels in PC12 cells stably transfected with APP695swe and PSEN1dE9. Intragastric administration of LPD for 3 months dose-dependently reversed cognitive deficits in APP/PS1 mice. LPD treatment substantially decreased hippocampal Aβ plaques in APP/PS1 mice and decreased the levels of Aβ40 and Aβ42 in vivo and in vitro. Moreover, LPD treatment induced mitophagy in vivo and in vitro and increased brain 18F-FDG uptake in APP/PS1 mice. LPD treatment significantly increased OCR, ATP production, maximal respiration, spare respiratory capacity, and basal respiration in APP/PS1 cells. Mechanistically, LPD treatment upregulated PPARγ, PINK1, and the phosphorylation of Parkin (Ser65) and increased the LC3-II/LC3-I ratio but decreased SQSTM1/p62 in vivo and in vitro. Importantly, all these protective effects mediated by LPD were abolished by cotreatment with the selective PPARγ antagonist GW9662. In summary, LPD could increase brain glucose metabolism and ameliorate cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.

CK2 regulates receptor-mediated mitophagy that removes damaged mitochondria. The PINK1/Parkin pathways also involve mitochondrial clearance through mitophagy. However, it is not clear whether CK2 regulates PINK1/Parkin-dependent mitophagy in response to stress. Rotenone treatment showed a decrease of FUNDC1 expression in the mitochondrial fraction of SH-SY5Y and HeLa cells, but an increase of PINK1/Parkin expression only in SH-SY5Y cells. Interestingly, CK2 inhibition increased mitochondrial LC3II expression in rotenone-treated HeLa cells, whereas it decreased in SH-SY5Y cells, indicating that CK2 mediates rotenone-induced mitophagy in dopaminergic neurons. Furthermore, FUNDC1 expression increased in rotenone-treated SH-SY5Y cells by CK2 inhibition, whereas it decreased in HeLa cells. CK2 inhibition also blocked the increase of Drp1, PINK1 and Parkin translocation into mitochondria and decrease of PGAM5 expression in rotenone-treated SH-SY5Y cells. As expected, rotenone treatment in PGAM5-knockdown cells reduced the expression of PINK1 and Parkin and decrease of LC3II expression. Interestingly, we observed that knockdown of CK2α or PGAM5 induced a further increase in caspase-3 expression. These results suggest that PINK1/Parkin-dependent mitophagy was dominant over FUNDC1 receptor-mediated mitophagy. Collectively, our findings suggest that CK2 can positively induce PINK1/Parkin-dependent mitophagy, and that mitophagy regulates cytoprotective effects by CK2 signaling in dopaminergic neurons. All data generated or analyzed during this study are available upon request. • Rotenone decreases mitochondrial complex I activity, resulting in mitochondrial dysfunction. • Rotenone induces the FUNDC1 receptor-mediated signaling as well as PINK1/Parkin-dependent mitophagy in SH-SY5Y cells. • CK2 mediates PINK1/Parkin-dependent mitophagy though PGAM5 and Drp1. • Mitophagy can regulate rotenone-induced toxicity through CK2 signaling pathway in dopaminergic neurons. [ABSTRACT FROM AUTHOR]

This study aimed to explore PINK1/Parkin's role in methanol metabolite formic acid‐induced autophagy in PC12 cells and provide a theoretical basis for elucidating methanol‐induced neurotoxicity. After treatment with different formic acid concentrations, we observed the morphology and mitochondria of PC12 cells. We used an ultra‐micro enzyme kit to detect the mitochondrial Na+‐K+‐ATPase and Ca2+‐Mg2+‐ATPase activities; a JC‐1 kit to detect changes in the mitochondrial membrane potential (MMP); MDC staining to detect the autophagy levels; and western blotting to measure the expression levels of the mitochondrial marker protein COX IV and the autophagy‐related proteins Beclin1, P62 and LC3II/LC3I, and the mitochondrial and cytoplasmic levels of PINK1, Parkin and P‐Parkin. Compared with the control group, the mitochondrial diameters, the mitochondrial Na+‐K+‐ATP and Ca2+‐Mg2+‐ATPase activities, the MMP, and the COX IV expression levels decreased significantly (P < 0.05). The fluorescence signal intensity (indicating autophagy); relative Beclin1 and LC3II/LC3I protein expression levels; and relative mitochondrial PINK1, Parkin and P‐Parkin levels increased significantly, and the relative P62 protein expression levels and relative cytoplasmic PINK1, Parkin and P‐Parkin levels decreased significantly (P < 0.05) compared with the control group. Thus, formic acid alters mitochondrial morphology, causes mitochondrial dysfunction, affects the PINK/Parkin pathway and, thus, activates the process of mitochondrial autophagy. [ABSTRACT FROM AUTHOR]

Excessive manganese (Mn) exposure produces neurotoxicity with mitochondrial damage. Mitophagy is a protective mechanism to eliminate damaged mitochondria to protect cells. The aim of this study was to determine the dose-response of Mn-induced mitochondria damage, the expression of mitophagy-mediated protein PINK1/Parkin and mitophagy in dopamine-producing SK-N-SH cells. Cells were exposed to 0, 300, 900, and 1500 μM Mn2+ for 24 h, and ROS production, mitochondrial damage and mitophagy were examined. The levels of dopamine were detected by ELISA and neurotoxicity and mitophagy-related proteins (α-synuclein, PINK1, Parkin, Optineurin, and LC3II/I) were detected by western blot. Mn increased intracellular ROS and apoptosis and decreased mitochondrial membrane potential in a concentration-dependent manner. However, at the low dose of 300 μM Mn, autophagosome was increased 11-fold, but at the high dose of 1500 μM, autophagosome was attenuated to 4-fold, together with decreased mitophagy-mediated protein PINK1/Parkin and LC3II/I ratio and increased Optineurin expression, resulting in increased α-synuclein accumulation and decreased dopamine production. Thus, Mn-induced mitophagy exhibited a novel biphasic regulation: at the low dose, mitophagy is activated to eliminate damaged mitochondria, however, at the high dose, cells gradually loss the adaptive machinery, the PINK1/Parkin-mediated mitophagy weakened, resulting in neurotoxicity. Graphical Abstract [ABSTRACT FROM AUTHOR]

One of the main pathological features of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra compacta (SNc). Cistanoside A (CA) has a strong neuroprotective effect in PD, but the exact mechanism is unclear. In the present study, the MPTP‐stimulated mouse model of PD and MPP+‐treated PD model in the MES23.5 neuronal cell model of PD were used to investigate the neuroprotective effects of CA on PD and its potential mechanism. The in vivo experiment results indicated that CA improved the motor function in mice and increased the number of tyrosine hydroxylase positive cells in SNc. In vitro experiments showed that CA reduced the MPP+‐induced decrease in neurons and mitochondrial membrane potential and promoted the activation of autophagosomes. Furthermore, we found that CA promoted the recruitment of PINK1 and Parkin aggregation to impair mitochondrial membranes and inhibited mitochondrial damage via LC3‐ and p62‐mediated autophagy. In conclusion, CA protects against MPTP‐induced neurotoxicity in vivo and MPP+‐induced neurotoxicity in vitro, possibly by promoting the PINK1/Parkin/p62 pathway to accelerate the degradation of damaged mitochondria thereby reducing oxidative stress. [ABSTRACT FROM AUTHOR]

Although treadmill exercise is effective against Alzheimer's disease (AD), the molecular mechanisms underlying these effects are not fully understood. Recent literature has linked the accumulation of damaged mitochondria and defective mitophagy to AD progression. Here, we determined that abnormally activated PINK1/Parkin pathway–mediated mitophagy plays an important role in AD progression and pathogenesis in 6-month-old APP/PS1 mice. We used the lysosomal inhibitor chloroquine and demonstrated that a 12-week treadmill exercise program improved mitochondrial function, decreased accumulation of β-amyloid plaques, and ameliorated loss of learning and memory ability by enhancing PINK1/Parkin-mediated mitophagy activity in the hippocampus of APP/PS1 mice. Moreover, using the SIRT1 inhibitor EX527, we found that 12 weeks of treadmill exercise rescued PINK1/Parkin-mediated mitophagy by activating the SIRT1-FOXO1/3 axis in the hippocampus of APP/PS1 mice. These findings reveal that activating PINK1/Parkin-mediated mitophagy is a promising strategy for AD treatment, and that the SIRT1-FOXO1/3 axis is a potential candidate for the development of mitophagy enhancers. [ABSTRACT FROM AUTHOR]

Our study aimed to detect the effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) on exacerbating cardiomyocyte hypoxia/reoxygenation (H/R) injury and the possible mechanism. A cell model of H/R was constructed. PCSK9 mRNA and protein levels were significantly upregulated during AC16 cardiomyocyte H/R. Flowmetry detection of apoptosis, as well as JC-1, confirmed that PCSK9 upregulation of autophagy levels was accompanied by apoptosis. Furthermore, in the H/R+si-PCSK9 group, the expression of autophagy-related protein LC3 decreased and P62 increased. At the same time, the presentation of the autophagic pathway Pink1/Parkin was also downregulated. In conclusion, in AC16 cardiomyocytes treated with H/R, PCSK9 expression and autophagy levels were increased; a possible molecular mechanism was the activation of the Pink1/Parkin pathway. [ABSTRACT FROM AUTHOR]

Mitophagy is a process by which cells selectively eliminate damaged or dysfunctional mitochondria through the autophagy-lysosome pathway, thereby maintaining mitochondrial quality and cellular homeostasis. This process is closely linked to the onset and progression of various heart diseases. Modern pharmacological research has demonstrated that phytochemicals can regulate mitochondrial homeostasis in cardiomyocytes through multiple mechanisms, influencing mitophagy and protecting cardiomyocytes, which in turn exerts anti-cardiovascular effects. However, the underlying mechanisms of these effects are not yet fully understood. This study summarizes the pharmacological effects and molecular mechanisms of mitophagy in heart diseases, aiming to provide reference for the research and treatment of phytochemicals targeting mitophagy against heart diseases. The results indicated that phytochemicals (such as Berberine, Ginsenoside Rg1, Quercetin, Resveratrol, Baicalein, and so on) can exert preventive and therapeutic effects on heart diseases (such as cardiac toxicity or damage, myocardial ischemia/reperfusion injury, heart failure, heart aging, cardiac hypertrophy, cardiomyopathy, and so on.) via regulating the PINK1/Parkin and FUNDC1-dependent mitophagy pathway. These compounds mainly exert their effects by regulating mitochondrial homeostasis, mitochondrial dynamics, mitochondrial oxidative stress, mitochondrial apoptosis, and mitochondrial energy metabolism. This study provides a reference that phytochemicals have effect on anti-cardiovascular effects by regulating mitophagy. However, further in-depth mechanistic and clinical research are needed in the future., (© 2025 John Wiley & Sons Ltd.)

Background: Sepsis-associated encephalopathy (SAE) leads to increased mortality. Hydrogen (H 2 ) has been proven to be effective in protecting against SAE. This study aimed to investigate the protective mechanism of a high concentration of H 2 (HCH) (67%) against SAE., Methods: A mouse sepsis model was established via cecal ligation and puncture (CLP). 67% H 2 was inhaled for 1 h at 1 h and 6 h after the operation. First, mice were randomly divided into 5 groups: Sham, CLP, CLP + CQ (a mitophagy inhibitor), CLP + H 2 , and CLP + H 2  + CQ. Seven-day survival, cognitive function, and hippocampal damage were assessed. Then, mice were randomly divided into four groups: Sham, CLP, CLP + UA (a mitophagy agonist), and CLP + H 2 . Seven-day survival was recorded, cognitive function was assessed via Y-maze and Morris water maze tests, and hippocampal damage was evaluated via Nissl staining. Phosphorylated tau, inflammatory factors, ATP, and antioxidant enzyme levels and mitochondrial membrane potential (MMP) were detected. Mitochondria were observed via transmission electron microscopy. The protein levels of the PINK1/Parkin pathway and STING-TBK-IRF3 pathway were detected via western blotting., Results: HCH inhalation improves 7-day survival and cognitive function in septic mice and reduces brain tissue damage, proinflammatory cytokine levels, and phosphorylated tau levels. These effects were reversed by a mitophagy inhibitor. HCH significantly improves mitochondrial function, enhances PINK1/Parkin-mediated mitophagy, and reduces the activity of the STING-TBK-IRF3 pathway in brain tissue., Conclusions: HCH inhalation effectively improved the survival rate of septic mice, alleviated SAE, and reduced tau phosphorylation. The mechanism may involve HCH enhancing PINK1/Parkin-mediated mitophagy, which inhibits the activity of the cGAS-STING-IRF3 pathway, thereby reducing neuroinflammation., (© 2025 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Resveratrol (RES), a natural polyphenolic compound, has garnered significant attention for its therapeutic potential in various pathological conditions. This review explores how RES modulates mitophagy-the selective autophagic degradation of mitochondria essential for maintaining cellular homeostasis. RES promotes the initiation and execution of mitophagy by enhancing PINK1/Parkin-mediated mitochondrial clearance, reducing reactive oxygen species production, and mitigating apoptosis, thereby preserving mitochondrial integrity. Additionally, RES regulates mitophagy through the activation of key molecular targets such as AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), deacetylases (SIRT1 and SIRT3), and mitochondrial quality control (MQC) pathways, demonstrating substantial therapeutic effects in multiple disease models. We provide a detailed account of the biosynthetic pathways, pharmacokinetics, and metabolic characteristics of RES, focusing on its role in mitophagy modulation and implications for medical applications. Potential adverse effects associated with its clinical use are also discussed. Despite its promising therapeutic properties, the clinical application of RES is limited by issues of bioavailability and pharmacokinetic profiles. Future research should concentrate on enhancing RES bioavailability and developing derivatives that precisely modulate mitophagy, thereby unlocking new avenues for disease therapy., (© 2025 John Wiley & Sons Ltd.)

Mitochondria dysfunction has been defined as one of the hallmarks of aging-related diseases as is characterized by the destroyed integrity, abnormal distribution and size, insufficient ATP supply, increased ROS production, and subsequently damage and oxidize the proteins, lipids and nucleic acid. Mitophagy, an efficient way of removing damaged or defective mitochondria by autophagy, plays a pivotal role in maintaining the mitochondrial quantity and quality control enabling the degradation of unwanted mitochondria, and thus rescues cellular homeostasis in response to stress. Accumulating evidence demonstrates that impaired mitophagy has been associated with many neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) in a variety of patients and disease models with neural death, oxidative stress and disturbed metabolism, either as the cause or consequence. These findings suggest that modulation of mitophagy may be considered as a valid therapeutic strategy in neurodegenerative diseases. In this review, we summarize recent findings on the mechanisms of mitophagy and its role in neurodegenerative diseases, with a particular focus on mitochondrial proteins acting as receptors that mediate mitophagy in these diseases. [ABSTRACT FROM AUTHOR]

PPARγ agonists have been proven to be neuroprotective in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we identified ligustrazine piperazine derivative (LPD) as a novel PPARγ agonist, which was detected by a dual-luciferase reporter assay system. LPD treatment dose-dependently reduced Aβ40 and Aβ42 levels in PC12 cells stably transfected with APP695swe and PSEN1dE9. Intragastric administration of LPD for 3 months dose-dependently reversed cognitive deficits in APP/PS1 mice. LPD treatment substantially decreased hippocampal Aβ plaques in APP/PS1 mice and decreased the levels of Aβ40 and Aβ42 in vivo and in vitro. Moreover, LPD treatment induced mitophagy in vivo and in vitro and increased brain 18F-FDG uptake in APP/PS1 mice. LPD treatment significantly increased OCR, ATP production, maximal respiration, spare respiratory capacity, and basal respiration in APP/PS1 cells. Mechanistically, LPD treatment upregulated PPARγ, PINK1, and the phosphorylation of Parkin (Ser65) and increased the LC3-II/LC3-I ratio but decreased SQSTM1/p62 in vivo and in vitro. Importantly, all these protective effects mediated by LPD were abolished by cotreatment with the selective PPARγ antagonist GW9662. In summary, LPD could increase brain glucose metabolism and ameliorate cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice. [ABSTRACT FROM AUTHOR]

As a central hub for cellular metabolism and intracellular signaling, the mitochondrion is a pivotal organelle, dysfunction of which has been linked to several human diseases including neurodegenerative disorders and in particular Parkinson's disease. An inherent challenge that mitochondria face is the continuous exposure to diverse stresses that increase their likelihood of dysregulation. In response, eukaryotic cells have evolved sophisticated quality control mechanisms to monitor, identify, repair, and/or eliminate abnormal or misfolded proteins within the mitochondrion and/or the dysfunctional mitochondrion itself. Chaperones identify unstable or otherwise abnormal conformations in mitochondrial proteins and can promote their refolding to recover their correct conformation and stability. However, if repair is not possible, the abnormal protein is selectively degraded to prevent potentially damaging interactions with other proteins or its oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin-proteasome system mediate the selective and targeted degradation of such abnormal or misfolded protein species. Mitophagy (a specific kind of autophagy) mediates the selective elimination of dysfunctional mitochondria, to prevent the deleterious effects of the dysfunctional organelles within the cell. Despite our increasing understanding of the molecular responses toward dysfunctional mitochondria, many key aspects remain relatively poorly understood. Here, we review the emerging mechanisms of mitochondrial quality control including quality control strategies coupled to mitochondrial import mechanisms. In addition, we review the molecular mechanisms regulating mitophagy, with an emphasis on the regulation of PINK1/Parkin-mediated mitophagy in cellular physiology and in the context of Parkinson's disease cell biology. [ABSTRACT FROM AUTHOR]

Exposure to lead (Pb), an environmental pollutant, is closely associated with the development of neurodegenerative disorders through oxidative stress induction and alterations in mitochondrial function. Damaged mitochondria could be one of the reasons for the progression of Alzheimer's Disease (AD). Mitophagy is vital in keeping the cell healthy. To know its role in Pb-induced AD, we investigated the PINK1/Parkin dependent pathway by studying specific mitophagy marker proteins such as PINK1 and Parkin in differentiated SH-SY5Y cells. Our data have indicated a significant reduction in the levels of PINK1 and Parkin in cells exposed to Pb and β–amyloid peptides, both Aβ (25-35) and Aβ (1-40) individually and in different combinations, resulting in defective mitophagy. Also, the study unravels the status of mitochondrial permeability transition pore (MPTP), mitochondrial mass, mitochondrial membrane potential (MMP) and mitochondrial ROS production in cells treated with individual and different combination of Pb and Aβ peptides. An increase in mitochondrial ROS production, enhanced MPTP opening, depolarization of membrane potential and reduced mitochondrial mass in the exposed groups were observed. Also, in the present study, we found that Pb and β–amyloid peptides could trigger apoptosis by activating the Bak protein, which releases the cytochrome c from mitochondria through MPTP that further activates the AIF (apoptosis inducing factor) and caspase-3 proteins in the cytosol. The above findings reveal the potential role of mechanisms like PINK1/Parkin mediated mitophagy and dysfunctional mitochondria mediated apoptosis in Pb induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Background. Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease without effective treatments. Mitochondrial dysfunction weakens the ability of mesenchymal stem cells (MSCs) to repair the distal lung epithelium, which is a probable pathogenesis of IPF. In previous research, we found that cinnamaldehyde (CA) can maintain the mitochondrial morphology of MSCs. Methods. This present study evaluated the effect and mechanism of CA on murine lung MSCs using the hydrogen peroxide model. Antioxidant effects and mitochondrial function were determined using flow cytometry. The mRNA levels of mitochondrial dynamics and the expressions of autophagy-related proteins were also detected. Results. CA can increase the levels of SOD, MMP and ATP, decrease the rate of ROS and apoptosis, and restore the mitochondrial structure. CA can also improve themRNA expression of MFN1, MFN2, FIS1, DRP1, OPA1, and PGC-1α, increase the expression of LC3 II and p62 and promote the PINK1/Parkin signaling pathway. Our results demonstrated that CA can control mitochondrial quality and avoid apoptosis, which may be associated with the regulation of the PINK1/Parkin signaling pathway. [ABSTRACT FROM AUTHOR]

Weimin Fan,1,2 Shixian Chen,1 Xianghui Wu,3 Junqing Zhu,1 Juan Li1,2 1Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 3Laboratory Animal Research Center, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Juan LiDepartment of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou North Road, Baiyun District, Guangzhou, People’s Republic of ChinaTel + 0086-020-61641675Fax +86 20 61648308Email lijuan@smu.edu.cnBackground: Gouty arthritis (GA) is a common inflammatory disease with pain caused by the deposition of monosodium urate (MSU) crystals into joints and surrounding tissues. Resveratrol (Res), derived from grapes and peanuts and the traditional Chinese medicine (TCM) Reynoutria japonica for GA, acts against oxidation and inflammation. The present study aimed to investigate the therapeutic effect and mechanism of Res on GA.Methods: Arthritis rat models, MSU-induced peritonitis mouse models, and inflammatory models of mouse bone marrow-derived macrophage (BMDM) were used in this study. Enzyme-linked immunosorbent assay (ELISA), JC-1, histopathological, immunofluorescence, flow cytometry, Western blot methods were applied to observe the effects of resveratrol on NLRP3 inflammasomes and mitophagy.Results: Res significantly improves the gait score and synovitis of rats with GA and inhibits the peritoneal inflammation induced by MSU. Res inhibits the MSU-induced activation of NLRP3 inflammasomes by reducing the levels of IL-1β, IL-18, and Caspase-1 and the pyroptosis of macrophages. In addition, Res raises the level of mitochondrial membrane potential, inhibits the expression of P62 and Pink1, enhances the expressions of LC3B-II, Parkin, and TOMM20, and promotes mitophagy, while mitophagy inhibitors reverse the inhibitory effect of Res on the activation of NLRP3 inflammasomes.Conclusion: Res significantly improves GA, and the underlying mechanism might be inhibiting the activation of NLRP3 inflammasomes by triggering the Pink1/Parkin pathway to promote mitophagy.Keywords: gouty arthritis, inflammation, macrophages, Pink1/Parkin

Hepatic ischemia-reperfusion (I/R) injury stands as a recurring clinical challenge in liver transplantation, leading to mitochondrial dysfunction and cellular imbalance. Mitochondria, crucial for hepatocyte metabolism, are significantly damaged during hepatic I/R and the extent of mitochondrial damage correlates with hepatocyte injury. PINK1/Parkin-mediated mitophagy, is a specialized form of cellular autophagy, that maintains mitochondrial quality by identifying and removing damaged mitochondria, thereby restoring cellular homeostasis. Taxifolin (TAX), a natural flavonoid, possesses antioxidant, anti-inflammatory and anticancer properties. This study aimed at investigating the effects of TAX on hepatic I/R and the underlying mechanisms. C57BL/6 mice were pretreated with TAX or vehicle control, followed by 60 min of 70% hepatic ischemia. After 6 h of reperfusion, the mice were euthanized. In vitro, TAX-pretreated primary hepatocytes were subjected to oxygen glucose deprivation/reperfusion (OGD/R). Hepatic I/R caused mitochondrial damage and apoptosis in hepatocytes, but TAX pretreatment mitigated these effects by normalizing mitochondrial membrane potential and inhibiting reducing apoptotic protein expression. TAX exerted its protective effects by enhancing mitophagy via the PINK1/Parkin pathway. Moreover, silencing the PINK1 gene in primary hepatocytes reversed the beneficial effects of TAX. The results of the study demonstrate that promoting mitophagy through the PINK1/Parkin pathway restores mitochondrial function and protects the liver from I/R, suggesting that it may have therapeutic potential for the treatment of hepatic I/R. [Display omitted] • Taxifolin protects hepatocytes against apoptosis and mitochondrial dysfunction associated with hepatic ischemia-reperfusion. • It alleviates hepatic ischemia-reperfusion injury through PINK1/Parkin-mediated mitophagy. • Silencing the PINK1 gene reverses the protective effects of taxifolin and exacerbates hepatic ischemia-reperfusion injury. • Taxifolin presents a promising novel therapeutic strategy for ameliorating hepatic ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Aims: The broad-spectrum anticancer drug doxorubicin (Dox) is associated with a high incidence of cardiotoxicity, which severely affects the clinical application of the drug and patients' quality of life. Here, we assess how Dox modulates myocardial energy and contractile function and this could aid the development of relevant protective drugs. Methods: Mice were subjected to doxorubicin and breviscapine treatment. Cardiac function was analyzed by echocardiography, and Dox-mediated signaling was assessed in isolated cardiomyocytes. The dual cardioprotective and anti-tumor actions of breviscapine were assessed in mouse breast tumor models. Results: We found that Dox disrupts myocardial energy metabolism by decreasing glucose uptake and increasing fatty acid oxidation, leading to a decrease in ATP production rate, an increase in oxygen consumption rate and oxidative stress, and further energy deficits to enhance myocardial fatty acid uptake and drive DIC development. Interestingly, breviscapine increases the efficiency of ATP production and restores myocardial energy homeostasis by modulating the serotonin-glucose-myocardial PI3K/AKT loop, increasing glucose utilization by the heart and reducing lipid oxidation. It enhances mitochondrial autophagy via the PINK1/Parkin pathway, eliminates damaged mitochondrial accumulation caused by Dox, reduces the degree of cardiac fibrosis and inflammation, and restores cardiac micro-environmental homeostasis. Importantly, its low inflammation levels reduce myeloid immunosuppressive cell infiltration, and this effect is synergistic with the anti-tumor effect of Dox. Conclusion: Our findings suggest that disruption of the cardiac metabolic network by Dox is an important driver of its cardiotoxicity and that serotonin is an important regulator of myocardial glucose and lipid metabolism. Myocardial energy homeostasis and timely clearance of damaged mitochondria synergistically contribute to the prevention of anthracycline-induced cardiotoxicity and improve the efficiency of tumor treatment. [ABSTRACT FROM AUTHOR]

Vanillic acid, a phenolic compound mainly obtained from the foot of Picrorhiza scrophulariiflora Pennell, has been demonstrated to possess a cardiovascular-protective effect in previous studies. However, there is lack of research on vanillic acid protecting cardiomyocytes from oxidative stress injury by mediating mitophagy. In the present study, oxidative stress injury in the H9c2 cell line was induced by H2O2. Our results confirmed that vanillic acid mitigated apoptosis and injury triggered by oxidative stress, evidenced by the decline in production of reactive oxygen species and malondialdehyde and level of lactate dehydrogenase and the increase of superoxide dismutase and glutathione. The use of vanillic acid could also improve the polarization of mitochondrial membrane potential and decrease the cellular calcium level. After treatment by vanillic acid, impaired autophagy flux and mitophagy were improved, and the length of mitochondria was restored. Vanillic acid increased the expression of PINK1, Parkin, Mfn2, and the ratio of LC3-II/LC3-I and decreased the expression of p62. But, under the intervention of mitophagy inhibitor 3-MA, vanillic acid could not change the expression of PINK1/Parkin/Mfn2 and downstream genes to affect cell autophagy, mitophagy, and mitochondrial function. Our findings suggested that vanillic acid activated mitophagy to improve mitochondrial function, in which the PINK1/Parkin/Mfn2 pathway could be the potential regulatory mechanism. [ABSTRACT FROM AUTHOR]

Mitochondria hold redox homeostasis and energy metabolism as a crucial factor during oocyte maturation, while the exposure of estrogenic mycotoxin zearalenone causes developmental incapacity in porcine oocyte. This study aimed to reveal a potential resistance of phytoalexin resveratrol against zearalenone during porcine oocyte maturation and whether its mechanism was related with PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy. Porcine oocytes were exposed to 20 μM zearalenone with or without 2 μM resveratrol during in vitro maturation. As for the results, zearalenone impaired ultrastructure of mitochondria, causing mitochondrial depolarization, oxidative stress, apoptosis and embryonic developmental incapacity, in which mitophagy was induced in response to mitochondrial dysfunction. Phytoalexin resveratrol enhanced mitophagy through PINK1/Parkin in zearalenone-exposed oocytes, manifesting as enhanced mitophagy flux, upregulated PINK1, Parkin, microtubule-associated protein light-chain 3 beta-II (LC3B-II) and downregulated substrates mitofusin 2 (MFN2), voltage-dependent anion channels 1 (VDAC1) and p62 expressions. Resveratrol redressed zearalenone-induced mitochondrial depolarization, oxidative stress and apoptosis, and accelerated mitochondrial DNA copy during maturation, which improved embryonic development. This study offered an antitoxin solution during porcine oocyte maturation and revealed the involvement of PINK1/Parkin-mediated mitophagy, in which resveratrol mitigated zearalenone-induced embryonic developmental incapacity. [ABSTRACT FROM AUTHOR]

Neuronal oxidative stress caused by mitochondrial dysfunction plays a crucial role in the development of Parkinson's disease (PD). Growing evidence shows that autophagy confers neuroprotection in oxidative-stress-associated PD. This work aims to investigate the involvement of TMEM166, an endoplasmic-reticulum-localized autophagy-regulating protein, in the process of PD-associated oxidative stress through the classic cellular PD model of neuroblastoma SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP+). Reactive oxygen species (ROS) production and mitochondrial membrane potential were checked to assess the oxidative stress induced by MPP+ and the cellular ATP generated was determined to evaluate mitochondrial function. The effect on autophagy induction was evaluated by analyzing p62 and LC3-II/I expression and by observing the LC3 puncta and the colocalization of LC3 with LAMP1/ LAMP2. The colocalization of mitochondria with LC3, the colocalization of Tom20 with LAMP1 and Tom20 expression were analyzed to evaluate mitophagy. We found that TMEM166 is up-regulated in transcript levels, but up-regulated first and then down-regulated by autophagic degradation in protein levels upon MPP+-treatment. Overexpression of TMEM166 induces mitochondria fragmentation and dysfunction and exacerbates MPP+-induced oxidative stress and cell viability reduction. Overexpression of TMEM166 is sufficient to induce autophagy and mitophagy and promotes autophagy and mitophagy under MPP+ treatment, while knockdown of TMEM166 inhibits basal autophagic degradation. In addition, overexpressed TMEM166 suppresses AMPK activation, while TMEM166 knockdown enhances AMPK activation. Pharmacological activation of AMPK alleviates the exacerbation of oxidative stress induced by TMEM166 overexpression and increases cell viability, while pharmacological inhibition mitophagy aggravates the oxidative stress induced by MPP+ treatment combined with TMEM166 overexpression. Finally, we find that overexpressed TMEM166 partially localizes to mitochondria and, simultaneously, the active AMPK in mitochondria is decreased. Collectively, these findings suggest that TMEM166 can translocate from ER to mitochondria and inhibit AMPK activation and, in response to mitochondrial oxidative stress, neuronal cells choose to up-regulate TMEM166 to promote autophagy/mitophagy; then, the enhancing autophagy/mitophagy degrades the TMEM166 to activate AMPK, by the two means to maintain cell survival. The continuous synthesis and degradation of TMEM166 in autophagy/mitochondria flux suggest that TMEM166 may act as an autophagy/mitochondria adaptor. [ABSTRACT FROM AUTHOR]

Cr (VI) is an extremely toxic environment and professional pollutant that seriously damages mitochondrial dysfunction when it enters a cell. Anthocyanins possess anti-oxidant, antiaging, and antifatigue properties. The regulatory effect of Lycium ruthenicum Murr anthocyanin (LRMA) on Cr (VI)-induced mitophagy in DF-1 cells was determined. The experimental design was divided into blank group, groups subjected to Cr (VI) and Cr (VI), and LRMA co-treatment groups. Cell viability was determined by the CCK-8 assay. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were assessed by flow cytometry and immunofluorescence. Mitophagy was monitored by ELISA and Western blot. Data showed that Cr (VI) caused the overexpression of autophagy-related proteins (LC3, Beclin-1) and reduced the expressions of autophagy protein p62 and TOMM20. Compared with the Cr (VI) group, the LRMA group showed considerably decreased mitochondrial damage and mitophagy. LRMA decreased the mitochondrial protein expression of PINK1 and Parkin's transfer from the cytoplasm to mitochondria. LRMA may confer protective effects by reducing PINK1/Parkin-mediated mitophagy in Cr (VI)-induced DF-1 cell models. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Among its pathologies, progressive loss of dopaminergic (DA) neurons in the substantia nigra is characteristic and contributes to many of the most severe symptoms of PD. Recent advances in induced pluripotent stem cell (iPSC) technology have made it possible to generate patient-derived DA neuronal cell culture and organoid models of PD. These models have contributed to understanding disease mechanisms and the identification of novel targets and therapeutic candidates. Still needed are better ways to model the age-related aspects of PD, as well as a deeper understanding of the interactions among disease-modifying genes and between genetic and environmental contributions to the etiology and progression of PD. Generation of iPSC lines and isogeneic controls from sporadic and genetic forms of Parkinson's disease (PD) have recapitulated many of the cellular disease phenotypes of PD in cell cultures. α-Synuclein (SNCA)-triplicate neurons and neurons derived from patients harboring the A53T mutation, neurons from leucine-rich repeat kinase 2 (LRRK2), PARK2/PARKIN, and phosphatase and tensin homolog induced putative kinase 1 (PINK1) iPSCs, and from patients with familial DJ-1 PD and other forms of PD, all show increased accumulation of α-synuclein. Mitochondrial defects, increased oxidative stress, lysosomal defects, and defects in endolysosomal transport are also observed in neurons derived from iPSC lines from patients with PD. One of the greatest challenges is that iPSC lines show substantial variability among clones. One way to overcome this problem is to generate multiple lines from each patient and compare lines, as well as to develop protocols that better reflect the effects of aging on neurons. [ABSTRACT FROM AUTHOR]