title: A LON-ClpP Proteolytic Axis Degrades Complex I to Extinguish ROS Production in Depolarized Mitochondria.
abstract: Mitochondrial 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.
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London WC1E 6BT, UK. Electronic address: kp296@leicester.ac.uk.
authors.forename: Kenneth Robert
authors.initials: KR
authors.lastname: Pryde
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London WC1E 6BT, UK.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Taanman
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London WC1E 6BT, UK.
authors.forename: Anthony Henry
authors.initials: AH
authors.lastname: Schapira
mesh_terms: D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063306:Mitophagy / Q000235:genetics*; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D042967:Electron Transport Complex I; D011494:Protein Kinases; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: ClpP; LON; NADH:ubiquinone oxidoreductase; complex I; mitochondria; mitochondrial proteases; mitophagy; retrograde signaling