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J Neurochem. 2018 Mar;144(6):691-709. doi: 10.1111/jnc.14308. Epub 2018 Feb 14.

Mitochondrial function and autophagy: integrating proteotoxic, redox, and metabolic stress in Parkinson's disease.

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Center for Free Radical Biology, Birmingham, Alabama, USA.
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Department of Veterans Affairs, Birmingham VA Medical Center, Birmingham, Alabama, USA.


Parkinson's disease (PD) is a movement disorder with widespread neurodegeneration in the brain. Significant oxidative, reductive, metabolic, and proteotoxic alterations have been observed in PD postmortem brains. The alterations of mitochondrial function resulting in decreased bioenergetic health is important and needs to be further examined to help develop biomarkers for PD severity and prognosis. It is now becoming clear that multiple hits on metabolic and signaling pathways are likely to exacerbate PD pathogenesis. Indeed, data obtained from genetic and genome association studies have implicated interactive contributions of genes controlling protein quality control and metabolism. For example, loss of key proteins that are responsible for clearance of dysfunctional mitochondria through a process called mitophagy has been found to cause PD, and a significant proportion of genes associated with PD encode proteins involved in the autophagy-lysosomal pathway. In this review, we highlight the evidence for the targeting of mitochondria by proteotoxic, redox and metabolic stress, and the role autophagic surveillance in maintenance of mitochondrial quality. Furthermore, we summarize the role of α-synuclein, leucine-rich repeat kinase 2, and tau in modulating mitochondrial function and autophagy. Among the stressors that can overwhelm the mitochondrial quality control mechanisms, we will discuss 4-hydroxynonenal and nitric oxide. The impact of autophagy is context depend and as such can have both beneficial and detrimental effects. Furthermore, we highlight the potential of targeting mitochondria and autophagic function as an integrated therapeutic strategy and the emerging contribution of the microbiome to PD susceptibility.


4-hydroxynonenal; bioenergetic health index; endosome-lysosomes; glucose metabolism; microglia; post-translational modification

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