Abstract
SummaryMitochondrial dysfunction is implicated in numerous neurodegenerative disorders and in Parkinson’s disease (PD) in particular. PINK1 and Parkin gene mutations are causes of autosomal recessive PD, and these respective proteins function cooperatively to degrade depolarized mitochondria (mitophagy). It is widely assumed that impaired mitophagy causes PD, as toxic reactive oxygen species (ROS)-producing mitochondria accumulate and progressively drive neurodegeneration. Instead, we report that a LON-ClpP proteolytic quality control axis extinguishes ROS in depolarized mitochondria by degrading the complex I ROS-generating domain. Complex I deficiency has also been identified in PD brain, and our study provides a compelling non-genetic mechanistic rationale to explain this observation: intact complex I depletes if mitochondrial bioenergetic capacity is robustly attenuated.
Highlights
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder (Schapira, 2008)
Mitochondrial Complex I Is Selectively Degraded in Depolarized Mitochondria To determine the fate of complex I in damaged organelles, we induced mitophagy using canonical methodology (Narendra et al, 2010), and we chemically depolarized mitochondria with the protonophore CCCP in SH-SY5Y and HeLa cells
The peripheral arm protrudes into the matrix and catalyzes NADH oxidation, reactive oxygen species (ROS) production, and ubiquinone reduction
Summary
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder (Schapira, 2008). Mitochondrial dysfunction is implicated in most PD genetic variants and is reported in sporadic PD, suggesting mitochondrial homeostasis and PD are connected (Schapira, 2008). Brains from sporadic PD patients typically display a selective deficiency in mitochondrial complex I activity (via an uncertain mechanism), and they comprise mitochondrial/cellular oxidative damage (Schapira et al, 1989; Keeney et al, 2006; Parker et al, 2008). PINK1-Parkin function cooperatively to degrade damaged/depolarized mitochondria via autophagy (mitophagy) (Narendra et al, 2010). PINK1 is the damage sensor; it is imported into the inner mitochondrial membrane (IMM) of polarized mitochondria and degraded. Mitochondrial depolarization terminates IMM import (Malhotra et al, 2013), so PINK1 rapidly accumulates in the outer mitochondrial membrane (OMM) and phospho-activates Parkin (Kane et al, 2014) to initiate mitophagy
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