title: Impaired OMA1-dependent cleavage of OPA1 and reduced DRP1 fission activity combine to prevent mitophagy in cells that are dependent on oxidative phosphorylation.
abstract: Mitochondrial dynamics play crucial roles in mitophagy-based mitochondrial quality control, but how these pathways are regulated to meet cellular energy demands remains obscure. Using non-transformed human RPE1 cells, we report that upregulation of mitochondrial oxidative phosphorylation alters mitochondrial dynamics to inhibit Parkin-mediated mitophagy. Despite the basal mitophagy rates remaining stable upon the switch to dependence on oxidative phosphorylation, mitochondria resist fragmentation when RPE1 cells are treated with the protonophore carbonyl cyanide m-chlorophenyl hydrazone. Mechanistically, we show that this is because cleavage of the inner membrane fusion factor L-OPA1 is prevented due to the failure to activate the inner membrane protease OMA1 in mitochondria that have a collapsed membrane potential. In parallel, mitochondria that use oxidative phosphorylation are protected from damage-induced fission through the impaired recruitment and activation of mitochondrial DRP1. Using OMA1-deficient MEF cells, we show that the preservation of a stable pool of L-OPA1 at the inner mitochondrial membrane is sufficient to delay mitophagy, even in the presence of Parkin. The capacity of cells that are dependent on oxidative phosphorylation to maintain substantial mitochondrial content in the face of acute damage has important implications for mitochondrial quality control in vivo.
authors.affiliation: Cell Biology Laboratories, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: Thomas D B
authors.initials: TD
authors.lastname: MacVicar
authors.affiliation: Cell Biology Laboratories, University of Bristol, University Walk, Bristol BS8 1TD, UK Jon.lane@bristol.ac.uk.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Lane
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D008666:Metalloendopeptidases; C477817:molecule metalloprotease-related protein-1, human; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; C110768:DNM1L protein, human; D034281:Dynamins
keywords: Autophagy; DRP1; Mitochondrial dynamics; Mitophagy; OMA1; OPA1