22 results on '"Sue, Carolyn M."'
Search Results
2. New insights into the complex role of mitochondria in Parkinson's disease.
- Author
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Grünewald A, Kumar KR, and Sue CM
- Subjects
- Animals, Humans, Mitochondria metabolism, Mitochondria pathology, Parkinson Disease physiopathology
- Abstract
New discoveries providing insights into mitochondrial bioenergetics, their dynamic interactions as well as their role in cellular homeostasis have dramatically advanced our understanding of the neurodegenerative process of Parkinson's disease (PD). Respiratory chain impairment is a key feature in sporadic PD patients and there is growing evidence that links proteins encoded by PD-associated genes to disturbances in mitochondrial function. Against the backdrop of latest advances in the development of PD treatments that target mitochondria, we aim to give an overview of the literature published in the last three decades on the significance of mitochondria in the pathogenesis of PD. We describe the contribution of mitochondrial genome alterations and PD-associated genes to mitochondrial maintenance. We highlight mitophagy as a key mechanism in neurodegeneration. Moreover, we focus on the reciprocal interaction between alpha-synuclein aggregation and mitochondrial dysfunction. We discuss a novel trafficking pathway involving mitochondrial-derived vesicles within the context of PD and provide a synopsis of the most recently emerging topics in PD research with respect to mitochondria. This includes the relationship between mitochondria and cell-mediated immunity, the ER-mitochondria axis, sirtuin-mediated mitochondrial stress response and the role of micro RNAs in the aetiology of PD. In addition, recent studies have challenged the neuro-centric view of PD pathology, moving microglia and astrocytes into the research spotlight. Greater insights into these mechanisms may hold the key for the development of novel targeted therapies, addressing the need for a disease-modifying treatment, which has remained elusive to date., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
3. Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants.
- Author
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Vulinovic F, Krajka V, Hausrat TJ, Seibler P, Alvarez-Fischer D, Madoev H, Park JS, Kumar KR, Sue CM, Lohmann K, Kneussel M, Klein C, and Rakovic A
- Subjects
- CRISPR-Cas Systems, Cell Culture Techniques, Cell Line, Tumor, Humans, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells metabolism, Microtubules metabolism, Neuroblastoma metabolism, Neuronal Outgrowth, Neurons metabolism, Phenotype, RNA Stability, RNA, Messenger chemistry, Tubulin chemistry, Tubulin metabolism, Kinesins metabolism, Mitochondria metabolism, Mutation, Neuroblastoma genetics, Neurons cytology, Tubulin genetics
- Abstract
Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum of diseases ranging from hereditary generalized dystonia with whispering dysphonia (DYT-TUBB4A) and hereditary spastic paraplegia (HSP) to leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). TUBB4A encodes the brain-specific β-tubulin isotype, β-tubulin 4A. To elucidate the pathogenic mechanisms conferred by TUBB4A mutations leading to the different phenotypes, we functionally characterized three pathogenic TUBB4A variants (c.4C>G,p.R2G; c.745G>A,p.D249N; c.811G>A, p.A271T) as representatives of the mutational and disease spectrum) in human neuroblastoma cells and human induced pluripotent stem cell (iPSC)-derived neurons. We showed that mRNA stability was not affected by any of the TUBB4A variants. Although two mutations (p.R2G and p.D249N) are located at the α/β-tubulin interdimer interface, we confirmed incorporation of all TUBB4A mutants into the microtubule network. However, we showed that the mutations p.D249N and p.A271T interfered with motor protein binding to microtubules and impaired neurite outgrowth and microtubule dynamics. Finally, TUBB4A mutations, as well as heterozygous knockout of TUBB4A, disrupted mitochondrial transport in iPSC-derived neurons. Taken together, our findings suggest that functional impairment of microtubule-associated transport is a shared pathogenic mechanism by which the TUBB4A mutations studied here cause a spectrum of diseases., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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4. Mitochondrial Dysfunction in Parkinson's Disease: New Mechanistic Insights and Therapeutic Perspectives.
- Author
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Park JS, Davis RL, and Sue CM
- Subjects
- Animals, Antiparkinson Agents pharmacology, Electron Transport drug effects, Electron Transport physiology, Humans, Mitochondria drug effects, Mitochondria genetics, Parkinson Disease genetics, Antiparkinson Agents therapeutic use, Mitochondria metabolism, Parkinson Disease drug therapy, Parkinson Disease metabolism
- Abstract
Purpose of Review: Parkinson's disease (PD) is a complex neurodegenerative disorder, the aetiology of which is still largely unknown. Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in PD pathophysiology. Here we review recent developments around mitochondrial dysfunction in familial and sporadic PD, with a brief overview of emerging therapies targeting mitochondrial dysfunction., Recent Findings: Increasing evidence supports the critical role for mitochondrial dysfunction in the development of sporadic PD, while the involvement of familial PD-related genes in the regulation of mitochondrial biology has been expanded by the discovery of new mitochondria-associated disease loci and the identification of their novel functions. Recent research has expanded knowledge on the mechanistic details underlying mitochondrial dysfunction in PD, with the discovery of new therapeutic targets providing invaluable insights into the essential role of mitochondria in PD pathogenesis and unique opportunities for drug development.
- Published
- 2018
- Full Text
- View/download PDF
5. Nix restores mitophagy and mitochondrial function to protect against PINK1/Parkin-related Parkinson's disease.
- Author
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Koentjoro B, Park JS, and Sue CM
- Subjects
- Adenosine Triphosphate biosynthesis, Aged, Asymptomatic Diseases, Carbonyl Cyanide m-Chlorophenyl Hydrazone pharmacology, Cell Line, Female, Fibroblasts drug effects, Fibroblasts metabolism, Fibroblasts pathology, Gene Expression Regulation, Humans, Membrane Proteins metabolism, Mitochondria drug effects, Mitochondria pathology, Mutation, Neurons drug effects, Neurons metabolism, Neurons pathology, Parkinson Disease metabolism, Parkinson Disease pathology, Primary Cell Culture, Protein Kinases metabolism, Proto-Oncogene Proteins metabolism, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Substantia Nigra metabolism, Substantia Nigra pathology, Tumor Suppressor Proteins metabolism, Ubiquitin-Protein Ligases antagonists & inhibitors, Ubiquitin-Protein Ligases metabolism, Membrane Proteins genetics, Mitochondria metabolism, Mitophagy genetics, Parkinson Disease genetics, Protein Kinases genetics, Proto-Oncogene Proteins genetics, Tumor Suppressor Proteins genetics, Ubiquitin-Protein Ligases genetics
- Abstract
Therapeutic targets are needed to develop neuroprotective treatments for Parkinson's disease (PD). Mitophagy, the selective autophagic elimination of dysfunctional mitochondria, is essential for the maintenance of mitochondrial integrity and is predominantly regulated by the PINK1/Parkin-mediated pathway. Loss of function mutations in Parkin and PINK1 cause an accumulation of dysfunctional mitochondria, leading to nigral neurodegeneration and early-onset PD with a high penetrance rate. We previously identified an asymptomatic homozygous Parkin mutation carrier who had not developed PD by her eighth decade despite the loss of functional Parkin. Here we discover a putative mechanism that protects her against PD. In contrast to Parkin-related PD patient-derived cells, the asymptomatic carrier cells show preserved mitochondrial function and mitophagy which is mediated by mitochondrial receptor Nip3-like protein X (Nix). Nix-mediated mitophagy was not affected by PINK1 knockdown. Both genetic and pharmacological induction of Nix restores mitophagy in PINK1- and Parkin-related PD patient cell lines, confirming its ability to induce mitophagy in the absence of PINK1/Parkin-mediated pathway. Moreover, Nix over-expression improves mitochondrial ATP production in these patient cells. Our results demonstrate that Nix can serve as an alternative mediator of mitophagy to maintain mitochondrial turnover, identifying Nix as a promising target for neuroprotective treatment in PINK1/Parkin-related PD.
- Published
- 2017
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6. Hereditary Parkinsonism-Associated Genetic Variations in PARK9 Locus Lead to Functional Impairment of ATPase Type 13A2.
- Author
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Park JS and Sue CM
- Subjects
- Adolescent, Age of Onset, Cations, Divalent, Gene Expression, Genes, Recessive, Humans, Ion Transport, Lipofuscin genetics, Lipofuscin metabolism, Lysosomes pathology, Mitochondria pathology, Neuronal Ceroid-Lipofuscinoses metabolism, Neuronal Ceroid-Lipofuscinoses pathology, Parkinsonian Disorders metabolism, Parkinsonian Disorders pathology, Protein Domains, Proton-Translocating ATPases chemistry, Proton-Translocating ATPases metabolism, Structure-Activity Relationship, Zinc metabolism, alpha-Synuclein genetics, alpha-Synuclein metabolism, Lysosomes metabolism, Mitochondria metabolism, Mutation, Neuronal Ceroid-Lipofuscinoses genetics, Parkinsonian Disorders genetics, Proton-Translocating ATPases genetics
- Abstract
Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of Parkinson's disease (PD) with juvenile onset of parkinsonism, often accompanied by extra clinical features such as supranuclear gaze palsy, dementia and generalised brain atrophy. Mutations in ATP13A2, associated with the PARK9 locus (chromosome 1p36) have been identified in KRS patients. ATP13A2 encodes a lysosomal P5B-type ATPase which has functional domains similar to other P-type ATPases which mainly transport cations. Consistently, recent studies suggest that human ATP13A2 may preferably regulate Zn2+, while ATP13A2 from other species have different substrate selectivity. Until now, fourteen mutations in ATP13A2 have been associated with KRS, while other mutations have been reported in association with neuronal ceroid lipofuscinosis (NCL) and early-onset PD. Experimentally, these disease- associated ATP13A2 mutations have been shown to confer loss-of-function to the protein by disrupting its protein structure and function to varying degrees, ranging from impairment in ATPase function to total loss of protein, confirming their pathogenicity. Loss of functional ATP13A2 has been shown to induce Zn2+ dyshomeostasis. Disturbances in Zn2+ homeostasis impair mitochondrial and lysosomal function which leads to loss of mitochondrial bioenergetic capacity and accumulation of lysosomal substrates such as α-synuclein and lipofuscin. Additionally, ATP13A2 appears to be involved in α-synuclein externalisation through its Zn2+-regulating activity. In this review, we will discuss all the reported KRS/NCL-associated ATP13A2 mutations along with several PD-associated mutations which have been experimentally assessed, in respect to their impact on the protein structure and function of ATP13A2., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)
- Published
- 2017
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7. Functional hyperspectral imaging captures subtle details of cell metabolism in olfactory neurosphere cells, disease-specific models of neurodegenerative disorders.
- Author
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Gosnell ME, Anwer AG, Cassano JC, Sue CM, and Goldys EM
- Subjects
- Cells, Cultured, Female, Humans, MELAS Syndrome pathology, Male, Mitochondria pathology, Olfactory Receptor Neurons pathology, Spheroids, Cellular pathology, MELAS Syndrome metabolism, Mitochondria metabolism, Olfactory Receptor Neurons metabolism, Spheroids, Cellular metabolism
- Abstract
Hyperspectral imaging uses spectral and spatial image information for target detection and classification. In this work hyperspectral autofluorescence imaging was applied to patient olfactory neurosphere-derived cells, a cell model of a human metabolic disease MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like syndrome). By using an endogenous source of contrast subtle metabolic variations have been detected between living cells in their full morphological context which made it possible to distinguish healthy from diseased cells before and after therapy. Cellular maps of native fluorophores, flavins, bound and free NADH and retinoids unveiled subtle metabolic signatures and helped uncover significant cell subpopulations, in particular a subpopulation with compromised mitochondrial function. Taken together, our results demonstrate that multispectral spectral imaging provides a new non-invasive method to investigate neurodegenerative and other disease models, and it paves the way for novel cellular characterisation in health, disease and during treatment, with proper account of intrinsic cellular heterogeneity., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
- Full Text
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8. Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction.
- Author
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Park JS, Koentjoro B, Veivers D, Mackay-Sim A, and Sue CM
- Subjects
- Autophagy, Biological Transport, Homeostasis, Humans, Mutation, Parkinsonian Disorders enzymology, Parkinsonian Disorders genetics, Parkinsonian Disorders physiopathology, Proton-Translocating ATPases genetics, Reactive Oxygen Species metabolism, Mitochondria metabolism, Parkinsonian Disorders metabolism, Proton-Translocating ATPases deficiency, Zinc metabolism
- Abstract
Human ATP13A2 (PARK9), a lysosomal type 5 P-type ATPase, has been associated with autosomal recessive early-onset Parkinson's disease (PD). ATP13A2 encodes a protein that is highly expressed in neurons and is predicted to function as a cation pump, although the substrate specificity remains unclear. Accumulation of zinc and mitochondrial dysfunction are established aetiological factors that contribute to PD; however, their underlying molecular mechanisms are largely unknown. Using patient-derived human olfactory neurosphere cultures, which harbour loss-of-function mutations in both alleles of ATP13A2, we identified a low intracellular free zinc ion concentration ([Zn(2+)]i), altered expression of zinc transporters and impaired sequestration of Zn(2+) into autophagy-lysosomal pathway-associated vesicles, indicating that zinc dyshomeostasis occurs in the setting of ATP13A2 deficiency. Pharmacological treatments that increased [Zn(2+)]i also induced the production of reactive oxygen species and aggravation of mitochondrial abnormalities that gave rise to mitochondrial depolarization, fragmentation and cell death due to ATP depletion. The toxic effect of Zn(2+) was blocked by ATP13A2 overexpression, Zn(2+) chelation, antioxidant treatment and promotion of mitochondrial fusion. Taken together, these results indicate that human ATP13A2 deficiency results in zinc dyshomeostasis and mitochondrial dysfunction. Our data provide insights into the molecular mechanisms of zinc dyshomeostasis in PD and its contribution to mitochondrial dysfunction with ATP13A2 as a molecular link between the two distinctive aetiological factors of PD.
- Published
- 2014
- Full Text
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9. ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome.
- Author
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Grünewald A, Arns B, Seibler P, Rakovic A, Münchau A, Ramirez A, Sue CM, and Klein C
- Subjects
- Adult, Female, Humans, Male, Fibroblasts metabolism, Mitochondria genetics, Mitochondrial Diseases genetics, Mutation genetics, Parkinsonian Disorders genetics, Proton-Translocating ATPases genetics
- Abstract
Mutations in ATP13A2 cause autosomal-recessive parkinsonism (Kufor-Rakeb syndrome; KRS). Because several other parkinsonism-associated proteins have been connected to mitochondrial function and mitophagy, we studied the impact of endogenous mutations in ATPase type 13A2 (ATP13A2) on mitochondria in fibroblasts from KRS patients compared with controls. In patients, we detected decreased adenosine triphosphate (ATP) synthesis rates, increased mitochondrial DNA levels, a higher frequency of mitochondrial DNA lesions, increased oxygen consumption rates, and increased fragmentation of the mitochondrial network. Importantly, overexpression of wild-type ATP13A2 rescued the respiration phenotype. These findings collectively suggest that ATP13A2 contributes to the maintenance of a healthy mitochondrial pool, supporting the hypothesis that impaired mitochondrial clearance represents an important pathogenic mechanism underlying KRS., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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10. The genetics of mitochondrial disease.
- Author
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Davis RL and Sue CM
- Subjects
- DNA metabolism, DNA, Mitochondrial metabolism, Humans, Kearns-Sayre Syndrome genetics, Leigh Disease genetics, MELAS Syndrome genetics, MERRF Syndrome genetics, Mitochondria metabolism, Mutation, Optic Atrophy, Hereditary, Leber genetics, Electron Transport genetics, Mitochondria genetics, Mitochondrial Diseases genetics
- Abstract
The discovery that defects in mitochondria and mitochondrial DNA could cause human disease has led to the development of a rapidly expanding group of disorders known as mitochondrial disease. Mitochondrial disease is so named because of the common feature of impaired mitochondrial function. The main function of the mitochondrion is to produce energy for the cell in the form of ATP. ATP is generated by the respiratory chain, a series of complex proteins that are located in the mitochondrial membrane, and are encoded for by both the mitochondrial and nuclear genomes. Consequently, mitochondrial disease can be caused by mutations in either mitochondrial or nuclear DNA. Given the distribution of mitochondria throughout the body, the specific properties of mitochondrial DNA, and the mitochondrion's dependence on nuclear genes for its normal function, the clinical presentation of mitochondrial disease can be highly variable. Thus, familiarity with typical clinical presentations and knowledge of the genes that contribute to mitochondrial function will aid the clinician in the recognition, diagnosis, and management of patients with this group of diverse disorders., (© Thieme Medical Publishers.)
- Published
- 2011
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11. Mutant Parkin impairs mitochondrial function and morphology in human fibroblasts.
- Author
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Grünewald A, Voges L, Rakovic A, Kasten M, Vandebona H, Hemmelmann C, Lohmann K, Orolicki S, Ramirez A, Schapira AH, Pramstaller PP, Sue CM, and Klein C
- Subjects
- Adenosine Triphosphate metabolism, Adult, Aged, Case-Control Studies, Cells, Cultured, Female, Fibroblasts cytology, Fibroblasts enzymology, Humans, Male, Membrane Potential, Mitochondrial, Middle Aged, Mitochondria enzymology, Mitochondria metabolism, Oxidative Stress, Parkinson Disease enzymology, Parkinson Disease genetics, Parkinson Disease metabolism, Fibroblasts metabolism, Mitochondria genetics, Mutation, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism
- Abstract
Background: Mutations in Parkin are the most common cause of autosomal recessive Parkinson disease (PD). The mitochondrially localized E3 ubiquitin-protein ligase Parkin has been reported to be involved in respiratory chain function and mitochondrial dynamics. More recent publications also described a link between Parkin and mitophagy., Methodology/principal Findings: In this study, we investigated the impact of Parkin mutations on mitochondrial function and morphology in a human cellular model. Fibroblasts were obtained from three members of an Italian PD family with two mutations in Parkin (homozygous c.1072delT, homozygous delEx7, compound-heterozygous c.1072delT/delEx7), as well as from two relatives without mutations. Furthermore, three unrelated compound-heterozygous patients (delEx3-4/duplEx7-12, delEx4/c.924C>T and delEx1/c.924C>T) and three unrelated age-matched controls were included. Fibroblasts were cultured under basal or paraquat-induced oxidative stress conditions. ATP synthesis rates and cellular levels were detected luminometrically. Activities of complexes I-IV and citrate synthase were measured spectrophotometrically in mitochondrial preparations or cell lysates. The mitochondrial membrane potential was measured with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide. Oxidative stress levels were investigated with the OxyBlot technique. The mitochondrial network was investigated immunocytochemically and the degree of branching was determined with image processing methods. We observed a decrease in the production and overall concentration of ATP coinciding with increased mitochondrial mass in Parkin-mutant fibroblasts. After an oxidative insult, the membrane potential decreased in patient cells but not in controls. We further determined higher levels of oxidized proteins in the mutants both under basal and stress conditions. The degree of mitochondrial network branching was comparable in mutants and controls under basal conditions and decreased to a similar extent under paraquat-induced stress., Conclusions: Our results indicate that Parkin mutations cause abnormal mitochondrial function and morphology in non-neuronal human cells.
- Published
- 2010
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12. Mitochondrial DNA haplogroups and age-related maculopathy.
- Author
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Jones MM, Manwaring N, Wang JJ, Rochtchina E, Mitchell P, and Sue CM
- Subjects
- Aged, Aged, 80 and over, Complement Factor H genetics, Female, Gene Frequency, Genetic Markers, Humans, Macular Degeneration epidemiology, Male, Middle Aged, New South Wales, Prevalence, Risk Factors, DNA, Mitochondrial genetics, Haplotypes, Macular Degeneration genetics, Mitochondria genetics
- Abstract
Objective: To investigate whether mitochondrial haplogroups are associated with age-related maculopathy (ARM)., Methods: We assessed the association between mitochondrial haplogroups and ARM in a population-based sample of 3509 persons aged 49 years or older residing west of Sydney. Retinal photographs of both eyes were taken (1999-2001) and subsequently graded for ARM following the Wisconsin grading system. Genetic analysis for mitochondrial DNA haplogroups was performed. Associations between these genetic markers and risk factors for ARM were assessed., Results: After adjusting for age, sex, and smoking, haplogroup H was associated with a reduced prevalence of any (early and late) ARM (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.58-0.97), early ARM (OR, 0.75; 95% CI, 0.57-0.98), and large distinct and indistinct soft drusen (OR, 0.70; 95% CI, 0.56-0.89). Haplogroup J was associated with a higher prevalence of large, soft distinct drusen (OR, 1.80; 95% CI, 1.18-2.73). Haplogroup U was associated with an increased prevalence of retinal pigment abnormalities (OR, 1.45; 95% CI, 1.11-1.91)., Conclusions: Our findings of associations between different haplogroup types and prevalent ARM or ARM lesions suggest that these haplogroups may be genetic markers indicative of an individual's susceptibility to ARM.
- Published
- 2007
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13. Pharmacological rescue of mitochondrial and neuronal defects in SPG7 hereditary spastic paraplegia patient neurons using high throughput assays.
- Author
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Wali, Gautam, Yan Li, Liyanage, Erandhi, Kumar, Kishore R., Day, Margot L., and Sue, Carolyn M.
- Subjects
FAMILIAL spastic paraplegia ,PEOPLE with paraplegia ,NEURONS ,MITOCHONDRIA ,INDUCED pluripotent stem cells ,DRUG repositioning ,BACK muscles - Abstract
SPG7 is the most common form of autosomal recessive hereditary spastic paraplegia (HSP). There is a lack of HSP-SPG7 human neuronal models to understand the disease mechanism and identify new drug treatments. We generated a human neuronal model of HSP-SPG7 using induced pluripotent stem (iPS) cell technology. We first generated iPS cells from three HSP-SPG7 patients carrying different disease-causing variants and three healthy controls. The iPS cells were differentiated to form neural progenitor cells (NPCs) and then from NPCs to mature cortical neurons. Mitochondrial and neuronal defects were measured using a high throughout imaging and analysis-based assay in live cells. Our results show that compared to control NPCs, patient NPCs had aberrant mitochondrial morphology with increased mitochondrial size and reduced membrane potential. Patient NPCs develop to form mature cortical neurons with amplified mitochondrial morphology and functional defects along with defects in neuron morphology - reduced neurite complexity and length, reduced synaptic gene, protein expression and activity, reduced viability and increased axonal degeneration. Treatment of patient neurons with Bz-423, a mitochondria permeability pore regulator, restored the mitochondrial and neurite morphological defects and mitochondrial membrane potential back to control neuron levels and rescued the low viability and increased degeneration in patient neurons. This study establishes a direct link between mitochondrial and neuronal defects in HSP-SPG7 patient neurons. We present a strategy for testing mitochondrial targeting drugs to rescue neuronal defects in HSP-SPG7 patient neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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14. PINK1 signalling in neurodegenerative disease
- Author
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Whiten, Daniel R, Cox, Dezerae, Sue, Carolyn M, Sue, Carolyn M [0000-0002-7853-3566], and Apollo - University of Cambridge Repository
- Subjects
Parkinsons disease ,PTEN induced putative kinase 1 ,Ubiquitin-Protein Ligases ,Mitochondrial Membranes ,Mitophagy ,Neurodegneration ,Humans ,Neurodegenerative Diseases ,Protein Kinases ,Mitochondria - Abstract
PTEN-induced kinase 1 (PINK1) impacts cell health and human pathology through diverse pathways. The strict processing of full-length PINK1 on the outer mitochondrial membrane populates a cytoplasmic pool of cleaved PINK1 (cPINK1) that is constitutively degraded. However, despite rapid proteasomal clearance, cPINK1 still appears to exert quality control influence over the neuronal protein homeostasis network, including protein synthesis and degradation machineries. The cytoplasmic concentration and activity of this molecule is therefore a powerful sensor that coordinates aspects of mitochondrial and cellular health. In addition, full-length PINK1 is retained on the mitochondrial membrane following depolarisation, where it is a powerful inducer of multiple mitophagic pathways. This function is executed primarily through the phosphorylation of several ubiquitin ligases, including its most widely studied substrate Parkin. Furthermore, the phosphorylation of both pro- and anti-apoptotic proteins by mitochondrial PINK1 acts as a pro-cellular survival signal when faced with apoptotic stimuli. Through these varied roles PINK1 directly influences functions central to cell dysfunction in neurodegenerative disease.
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- 2022
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15. Healthcare resource utilization of patients with mitochondrial disease in an outpatient hospital setting.
- Author
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Haque, Sameen, Crawley, Karen, Shrestha, Rupendra, Schofield, Deborah, and Sue, Carolyn M.
- Subjects
MITOCHONDRIAL DNA ,MITOCHONDRIA ,NUCLEAR DNA ,MEDICAL care costs ,GENETIC disorder diagnosis - Abstract
Background and objectives: Mitochondrial diseases present as multi-system disorders requiring a comprehensive multidisciplinary approach. The data on healthcare resource utilization associated with mitochondrial diseases and the clinical drivers of these costs are limited including for the out-patient setting where the majority of the clinical care for mitochondrial disease patients occurs. We performed a cross-sectional retrospective study of out-patient healthcare resource utilization and costs for patients with a confirmed diagnosis of mitochondrial disease. Methods: We recruited participants from the Mitochondrial Disease Clinic in Sydney and stratified them into three groups: those with mitochondrial DNA (mtDNA) mutations (Group 1), those with nuclear DNA (nDNA) mutations and the predominant phenotype of chronic progressive external ophthalmoplegia (CPEO) or optic atrophy (Group 2) and those without a confirmed genetic diagnosis but clinical criteria and muscle biopsy findings supportive of a diagnosis of mitochondrial disease (Group 3). Data was collected through retrospective chart review and out-patient costs were calculated using the Medicare Benefits Schedule. Results: We analyzed the data from 91 participants and found that Group 1 had the greatest average out-patient costs per person per annum ($838.02; SD 809.72). Neurological investigations were the largest driver of outpatient healthcare costs in all groups (average costs per person per annum:—Group 1: $364.11; SD 340.93, Group 2: $247.83; SD 113.86 and Group 3: $239.57; SD 145.69) consistent with the high frequency (94.5%) of neurological symptoms. Gastroenterological and cardiac-related out-patient costs were also major contributors to out-patient healthcare resource utilization in Groups 1 and 3. In Group 2, ophthalmology was the second-most resource intensive specialty ($136.85; SD 173.35). The Group 3 had the greatest average healthcare resource utilization per person over the entire duration of out-patient clinic care ($5815.86; SD 3520.40) most likely due to the lack of a molecular diagnosis and a less customized management approach. Conclusion: The drivers of healthcare resource utilization are dependent on the phenotype–genotype characteristics. Neurological, cardiac, and gastroenterological costs were the top three drivers in the out-patient clinics unless the patient had nDNA mutations with predominant phenotype of CPEO and/or optic atrophy wherein ophthalmological-related costs were the second most resource intensive driver. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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16. Supplemental oxygen and muscle metabolism in mitochondrial myopathy patients
- Author
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Trenell, Michael I., Sue, Carolyn M., Thompson, Campbell H., and Kemp, Graham J.
- Published
- 2007
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17. Mitochondrial donation: is Australia ready?
- Author
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Dziadek, Marie A and Sue, Carolyn M
- Subjects
MELAS syndrome ,MITOCHONDRIA ,MITOCHONDRIAL DNA ,NUCLEAR DNA ,WOLFF-Parkinson-White syndrome ,CELL physiology - Published
- 2022
- Full Text
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18. New insights into the complex role of mitochondria in Parkinson's disease
- Author
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Anne Grünewald, Kumar, Kishore R., Sue, Carolyn M., Fonds National de la Recherche - FnR [sponsor], German Research Foundation - DFG [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Molecular and Functional Neurobiology (Grünewald Group) [research center]
- Subjects
Parkinson's disease ,Biochemistry, biophysics & molecular biology [F05] [Life sciences] ,Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant] ,Mitochondria - Abstract
New discoveries providing insights into mitochondrial bioenergetics, their dynamic interactions as well as their role in cellular homeostasis have dramatically advanced our understanding of the neurodegenerative process of Parkinson's disease (PD). Respiratory chain impairment is a key feature in sporadic PD patients and there is growing evidence that links proteins encoded by PD-associated genes to disturbances in mitochondrial function. Against the backdrop of latest advances in the development of PD treatments that target mitochondria, we aim to give an overview of the literature published in the last three decades on the significance of mitochondria in the pathogenesis of PD. We describe the contribution of mitochondrial genome alterations and PD-associated genes to mitochondrial maintenance. We highlight mitophagy as a key mechanism in neurodegeneration. Moreover, we focus on the reciprocal interaction between alpha-synuclein aggregation and mitochondrial dysfunction. We discuss a novel trafficking pathway involving mitochondrial-derived vesicles within the context of PD and provide a synopsis of the most recently emerging topics in PD research with respect to mitochondria. This includes the relationship between mitochondria and cell-mediated immunity, the ER-mitochondria axis, sirtuin-mediated mitochondrial stress response and the role of micro RNAs in the aetiology of PD. In addition, recent studies have challenged the neuro-centric view of PD pathology, moving microglia and astrocytes into the research spotlight. Greater insights into these mechanisms may hold the key for the development of novel targeted therapies, addressing the need for a disease-modifying treatment, which has remained elusive to date.
- Published
- 2019
19. Mitochondrial Function in Hereditary Spastic Paraplegia: Deficits in SPG7 but Not SPAST Patient-Derived Stem Cells.
- Author
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Wali, Gautam, Kumar, Kishore Raj, Liyanage, Erandhi, Davis, Ryan L., Mackay-Sim, Alan, and Sue, Carolyn M.
- Subjects
MITOCHONDRIAL pathology ,FAMILIAL spastic paraplegia ,STEM cells ,EPICATECHIN ,OXIDATIVE phosphorylation ,MEMBRANE potential ,MITOCHONDRIAL membranes ,CELL proliferation - Abstract
Mutations in SPG7 and SPAST are common causes of hereditary spastic paraplegia (HSP). While some SPG7 mutations cause paraplegin deficiency, other SPG7 mutations cause increased paraplegin expression. Mitochondrial function has been studied in models that are paraplegin-deficient (human, mouse, and Drosophila models with large exonic deletions, null mutations, or knockout models) but not in models of mutations that express paraplegin. Here, we evaluated mitochondrial function in olfactory neurosphere-derived cells, derived from patients with a variety of SPG7 mutations that express paraplegin and compared them to cells derived from healthy controls and HSP patients with SPAST mutations, as a disease control. We quantified paraplegin expression and an extensive range of mitochondrial morphology measures (fragmentation, interconnectivity, and mass), mitochondrial function measures (membrane potential, oxidative phosphorylation, and oxidative stress), and cell proliferation. Compared to control cells, SPG7 patient cells had increased paraplegin expression, fragmented mitochondria with low interconnectivity, reduced mitochondrial mass, decreased mitochondrial membrane potential, reduced oxidative phosphorylation, reduced ATP content, increased mitochondrial oxidative stress, and reduced cellular proliferation. Mitochondrial dysfunction was specific to SPG7 patient cells and not present in SPAST patient cells, which displayed mitochondrial functions similar to control cells. The mitochondrial dysfunction observed here in SPG7 patient cells that express paraplegin was similar to the dysfunction reported in cell models without paraplegin expression. The p.A510V mutation was common to all patients and was the likely species associated with increased expression, albeit seemingly non-functional. The lack of a mitochondrial phenotype in SPAST patient cells indicates genotype-specific mechanisms of disease in these HSP patients. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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20. Commentary: Nix restores mitophagy and mitochondrial function to protect against PINK1/Parkin-related Parkinson's disease.
- Author
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Jin-Sung Park, Koentjoro, Brianada, and Sue, Carolyn M.
- Subjects
MITOCHONDRIA ,PARKINSON'S disease ,ROTIGOTINE - Published
- 2017
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21. Mitochondrial DNA Deletion in a Child With Megaloblastic Anemia and Recurrent Encephalopathy.
- Author
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Akman, Cigdem Inan, Sue, Carolyn M., Shanske, Sara, Tanji, Kurenai, Bonilla, Eduardo, Ojaimi, Joceline, Krishna, Sindu, Schubert, Romaine, and DiMauro, Salvatore
- Subjects
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MITOCHONDRIAL DNA , *BLOOD diseases , *MITOCHONDRIA , *SEPSIS , *TRANSFER RNA , *AMINO acids - Abstract
A 3½-year-old boy presented with megaloblastic anemia and recurrent episodes of severe lactic acidosis and coma. At age 4 years, he developed sepsis and died; postmortem examination failed to show any gross abnormality in any tissue. Biochemical analysis of muscle showed decreased activities for all respiratory chain enzymes except complex II. Muscle histochemistry revealed diffuse cytochrome c oxidase deficiency. Southern blot analysis of mitochondrial DNA from muscle, liver, and blood showed a heteroplasmic single mitochindrial DNA deletion of 2.4 kb, which removed the genes for cytochrome c oxidase I and II and the transfer ribonucleic acid genes for serine and aspartic acid. Single large-scale deletions in mitochondrial DNA have been associated with Pearson's syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. This patient's presentation is unusual and suggests an overlap between Pearson's syndrome and Kearns-Sayre syndrome. (J Child Neurol 2004:19:258-261). [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
22. Mitochondrial disease in adults: recent advances and future promise.
- Author
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Ng, Yi Shiau, Bindoff, Laurence A, Gorman, Gráinne S, Klopstock, Thomas, Kornblum, Cornelia, Mancuso, Michelangelo, McFarland, Robert, Sue, Carolyn M, Suomalainen, Anu, Taylor, Robert W, Thorburn, David R, and Turnbull, Doug M
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MITOCHONDRIAL pathology , *ADULTS , *MITOCHONDRIA , *NUCLEOTIDE sequencing , *REPRODUCTIVE technology , *SMALL molecules - Abstract
Mitochondrial diseases are some of the most common inherited neurometabolic disorders, and major progress has been made in our understanding, diagnosis, and treatment of these conditions in the past 5 years. Development of national mitochondrial disease cohorts and international collaborations has changed our knowledge of the spectrum of clinical phenotypes and natural history of mitochondrial diseases. Advances in high-throughput sequencing technologies have altered the diagnostic algorithm for mitochondrial diseases by increasingly using a genetics-first approach, with more than 350 disease-causing genes identified to date. While the current management strategy for mitochondrial disease focuses on surveillance for multisystem involvement and effective symptomatic treatment, new endeavours are underway to find better treatments, including repurposing current drugs, use of novel small molecules, and gene therapies. Developments made in reproductive technology offer women the opportunity to prevent transmission of DNA-related mitochondrial disease to their children. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
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