Converging pathways in neurodegeneration, from genetics to mechanisms

Nature Neuroscience, Год журнала: 2018, Номер 21(10), С. 1300 - 1309

Опубликована: Сен. 19, 2018

Язык: Английский

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Mitochondrial biogenesis and clearance: a balancing act

FEBS Journal, Год журнала: 2016, Номер 284(2), С. 183 - 195

Опубликована: Июль 27, 2016

Mitochondria are semi-autonomous organelles of prokaryotic origin that postulated to have been acquired by eukaryotic cells through an early endosymbiotic event. Except for their main role in energy production, they also implicated fundamental cellular processes, including ion homeostasis, lipid metabolism, and initiation apoptotic cell death. Perturbed mitochondrial function has correlated with severe human pathologies such as type-2 diabetes, cardiovascular, neurodegenerative diseases. Thus, proper physiology is a prerequisite health survival. Cells developed sophisticated elaborate mechanisms adapt stress conditions alterations metabolic demands, regulating number function. Hence, the generation new removal damaged or unwanted mitochondria highly regulated processes need be accurately coordinated maintenance homeostasis. Here, we survey recent research findings advance our understanding highlight importance underlying molecular mechanisms.

Язык: Английский

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Aging and Autophagy in the Heart

Circulation Research, Год журнала: 2016, Номер 118(10), С. 1563 - 1576

Опубликована: Май 12, 2016

The aging population is increasing in developed countries. Because the incidence of cardiac disease increases dramatically with age, it important to understand molecular mechanisms through which heart becomes either more or less susceptible stress. Cardiac characterized by presence hypertrophy, fibrosis, and accumulation misfolded proteins dysfunctional mitochondria. Macroautophagy (hereafter referred as autophagy) a lysosome-dependent bulk degradation mechanism that essential for intracellular protein organelle quality control. Autophagy autophagic flux are generally decreased hearts, murine autophagy loss-of-function models develop exacerbated dysfunction accompanied organelles. On contrary, stimulation improves function mouse aggregation removing accumulated proteins, mitochondria, damaged DNA, thereby improving overall cellular environment alleviating aging-associated pathology heart. Increasing lines evidence suggest required many mediate lifespan extension, such caloric restriction, various organisms. These results raise exciting possibility may play an role combating adverse effects In this review, we discuss during aging, how alleviates age-dependent changes heart, level can be restored.

Язык: Английский

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PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease

Molecular Neurodegeneration, Год журнала: 2020, Номер 15(1)

Опубликована: Март 13, 2020

Abstract That certain cell types in the central nervous system are more likely to undergo neurodegeneration Parkinson’s disease is a widely appreciated but poorly understood phenomenon. Many vulnerable subpopulations, including dopamine neurons substantia nigra pars compacta, have shared phenotype of large, distributed axonal networks, dense synaptic connections, and high basal levels neural activity. These features come at substantial bioenergetic cost, suggesting that these experience degree mitochondrial stress. In such context, mechanisms quality control play an especially important role maintaining neuronal survival. this review, we focus on understanding unique challenges faced by mitochondria summarize evidence dysfunction contributes pathogenesis death subpopulations. We then review mediated activation PINK1 Parkin, two genes carry mutations associated with autosomal recessive disease. conclude pinpointing critical gaps our knowledge Parkin function, propose connection between sporadic defects will lead us greater insights into question selective vulnerability.

Язык: Английский

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The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications

Genes & Development, Год журнала: 2015, Номер 29(10), С. 989 - 999

Опубликована: Май 15, 2015

Two Parkinson's disease (PD)-associated proteins, the mitochondrial kinase PINK1 and E3-ubiquitin (Ub) ligase PARKIN, are central to quality control. In this pathway, accumulates on defective mitochondria, eliciting translocation of PARKIN from cytosol mediate clearance damaged mitochondria via autophagy (mitophagy). Throughout different stages mitophagy, post-translational modifications (PTMs) critical for regulation activity function. Indeed, activation recruitment onto involves PINK1-mediated phosphorylation both Ub. Through a stepwise cascade, is converted an autoinhibited enzyme into active phospho-Ub-dependent E3 ligase. Upon activation, ubiquitinates itself in concert with many substrates. The Ub conjugates attached these substrates can turn be phosphorylated by PINK1, which triggers further cycles activation. This feed-forward amplification loop regulates mitophagy. However, precise steps sequence PTMs cascade only now being uncovered. For instance, assembled consist predominantly noncanonical K6-linked chains. Moreover, reversible disassembled deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, USP30. impede DUBs, adding new layer complexity PARKIN-mediated mitophagy PTMs. It therefore evident that insight how regulate PINK1–PARKIN pathway will our understanding

Язык: Английский

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