New insights into the complex role of mitochondria in Parkinson's disease. (June 2019)

• Record Type: Journal Article
• Authors: Grünewald, Anne; Kumar, Kishore R.; Sue, Carolyn M.
• Is Part Of: Progress in neurobiology. Volume 177(2019)
• Page Start: 73
• Page End: 93
• Publication Date: 2019-06
• Subjects: ATP adenosine triphosphate -- ATP13A2 ATPase 13A2 -- CD cluster of differentiation -- COS CV-1 in origin with SV40 genes -- COX cytochrome c oxidase -- DAT dopamine transporter -- D-loop displacement loop -- DMF dimethylfumarate -- DNA deoxyribonucleic acid -- ERK2 extracellular signal-regulated kinase 2 -- FOXO3a forkhead box protein O3 -- GSH reduced glutathione -- HSP heat shock protein -- iNOS inducible nitric oxide synthase -- IPD idiopathic Parkinson's disease -- iPSC induced pluripotent stem cell -- LRRK2 leucine-rich repeat kinase 2 -- MAM mitochondria-associated endoplasmic reticulum membrane -- MB methylene blue -- MDV mitochondrial-derived vesicle -- MFN1/2 mitofusin1/2 -- MHC major histocompatibility complex -- MitAP mitochondrial antigen presentation -- MMF monomethylfumarate -- MPP+ 1-methyl-4-phenyl-4propionoxy-piperine, 1-methyl-4-phenylpyridinium -- MPPP 1-methyl-4-phenyl-4propionoxy-piperine -- MPTP 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine -- mtDNA mitochondrial DNA -- MVBs multi-vesicular bodies -- NAC N-acetylcysteine -- NdufA10 NADH: ubiquinone oxidoreductase subunit A10 -- Nrf2 nuclear factor erythroid 2-related factor 2 -- 6-OHDA 6-hydroxydopamine -- OPA1 optic atrophy 1 -- OPTN optineurin -- p62 sequestosome 1 -- PD Parkinson's disease -- PFF preformed alpha-synuclein fibrils -- PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha -- PINK1 PTEN-induced putative kinase 1 -- POLG mitochondrial polymerase gamma -- PTPIP51 protein tyrosine phosphatase-interacting protein 51 -- RNS reactive nitrogen species -- ROS reactive oxygen species -- SDH succinate dehydrogenase -- SIRT sirtuin -- SN substantia nigra -- SOD superoxide dismutase -- TFAM mitochondrial transcription factor A -- TFB2M mitochondrial transcription factor B2 -- TH tyrosine hydroxylase -- TIM translocase of inner membrane -- TNT tunnelling nanotube -- TOM translocase of outer membrane -- Ub ubiquitin -- UPRmt mitochondrial unfolded protein response -- VAPB vesicle-associated membrane protein-associated protein B -- VDAC1 voltage-dependent anion-selective channel 1 -- VPS35 vacuolar protein sorting-associated protein 35; Parkinson's disease -- Mitochondria -- Respiratory chain complexes -- Mitophagy -- Mitochondrial-derived vesicles -- Micro RNA -- Neurodegeneration -- Endogenous PD models -- iPSC-derived neurons -- Fibroblasts -- Glia cells; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2018.09.003
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: Mitochondrial DNA abnormalities in the substantia nigra are associated with respiratory chain dysfunction. There is a reciprocal interaction between alpha-synuclein aggregation and mitochondrial dysfunction. There is strong evidence supporting a role for impaired mitophagy and mitochondrial biogenesis in Parkinson's disease. Mitochondrial, mtDNA maintenance and lysosomal disease mechanisms may converge at the level of cell-mediated immunity. Mitochondrial dysfunction is a target for novel drug therapies, although most clinical trials have failed to show benefit. 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.