Abstract
ABSTRACTMitochondrial 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.
Highlights
Mitochondria are highly dynamic organelles that generate ATP through oxidative phosphorylation (OXPHOS), contribute to lipid and Ca2+ homeostasis, and mediate and/or amplify cellular apoptotic responses (Youle and van der Bliek, 2012)
Parkin-mediated mitophagy is suppressed in OXPHOSdependent RPE1 cells To explore the relationships between mitochondrial network dynamics and quality control, we measured mitophagy in several human cell lines that stably expressed yellow fluorescent protein (YFP)-tagged Parkin and found human telomerase immortalised retinal pigment epithelial cells to be the most efficient (80–90% cells depleted all mitochondria within 24 hours of treatment with carbonyl cyanide m-chlorophenyl hydrazone (CCCP); supplementary material Fig. S1)
Here, we have explored the relationship between mitochondrial OXPHOS activity and mitophagy, and found that increased cellular dependency on OXPHOS causes a profound block of stress-induced mitophagy at the level of mitochondrial dynamics
Summary
Mitochondria are highly dynamic organelles that generate ATP through oxidative phosphorylation (OXPHOS), contribute to lipid and Ca2+ homeostasis, and mediate and/or amplify cellular apoptotic responses (Youle and van der Bliek, 2012). Cell Biology Laboratories, University of Bristol, University Walk, Bristol BS8 1TD, UK. Disturbances in the relationship between quality control and energy homeostasis contribute to disease (Gautier et al, 2008; Youle and Narendra, 2011), highlighting the importance of understanding how cellular energy demands and mitophagy are coupled
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