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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.

SUBMITTER: MacVicar TD

PROVIDER: S-EPMC4021475 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Impaired OMA1-dependent cleavage of OPA1 and reduced DRP1 fission activity combine to prevent mitophagy in cells that are dependent on oxidative phosphorylation.

MacVicar Thomas D B TD Lane Jon D JD

Journal of cell science 20140314 Pt 10

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 fragmentatio ...[more]

PMID: 24634514

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Project description:FUN14 domain-containing protein 1 (Fundc1)-dependent mitophagy, mainly activated by ischemic/hypoxic preconditioning, benefits acute myocardial reperfusion injury and chronic metabolic syndrome via sustaining mitochondrial homeostasis. Mitochondrial fission plays a pathogenic role in ischemic acute kidney injury (AKI) through perturbation of mitochondrial quality and activation of mitochondrial apoptosis. The aim of our study was to explore the role of Fundc1 mitophagy in ischemia preconditioning (IPC)-mediated renoprotection. Proximal tubule-specific Fundc1 knockout (Fundc1PTKO) mice were subjected to ischemia reperfusion injury (IRI) and IPC prior to assessment of renal function, mitophagy, mitochondrial quality control, and Drp1-related mitochondrial fission. Following exposure to IPC, Fundc1 mitophagy was activated through post-transcriptional phosphorylation at Ser17. Interestingly, IRI-mediated renal injury, inflammation, and tubule cell death were mitigated by IPC whereas proximal tubule-specific Fundc1 knockout (Fundc1PTKO) mice abolished IPC-offered renoprotection. Mechanistically, IRI-evoked mitochondrial damage was improved by IPC whereas Fundc1 deficiency provoked mitochondrial abnormality, manifested by impaired mitochondrial quality and hyperactivated Drp1-dependent mitochondrial fission. Interestingly, Fundc1 deficiency-associated mitochondrial dysfunction was reversed by pharmacological inhibition of mitochondrial fission. In vivo, Fundc1 deletion-caused renal injury, severe pro-inflammatory response, and tubule cell death could be nullified by way of knockout Drp1 on Fundc1PTKO background. Finally, we also revealed that IPC triggered Fundc1 mitophagy activation through UNC-51-like kinase 1 (Ulk1) and Ulk1 ablation interrupted IPC-mediated Fundc1 activation and thus attenuated IPC-induced renoprotection. Fundc1 mitophagy, primarily driven by IPC, confers resistance to AKI through reconciliation of mitochondrial fission, implicating the therapeutic potential of targeting mitochondrial homeostasis for AKI.

Project description:RATIONALE:Cardiac lipotoxicity, characterized by increased uptake, oxidation, and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes mellitus. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood. OBJECTIVE:To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. METHODS AND RESULTS:Using a transgenic mouse model of cardiac lipotoxicity overexpressing ACSL1 (long-chain acyl-CoA synthetase 1) in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation in isolated mitochondria. Mitochondrial morphological changes and elevated ROS generation are also observed in palmitate-treated neonatal rat ventricular cardiomyocytes. Palmitate exposure to neonatal rat ventricular cardiomyocytes initially activates mitochondrial respiration, coupled with increased mitochondrial polarization and ATP synthesis. However, long-term exposure to palmitate (>8 hours) enhances ROS generation, which is accompanied by loss of the mitochondrial reticulum and a pattern suggesting increased mitochondrial fission. Mechanistically, lipid-induced changes in mitochondrial redox status increased mitochondrial fission by increased ubiquitination of AKAP121 (A-kinase anchor protein 121) leading to reduced phosphorylation of DRP1 (dynamin-related protein 1) at Ser637 and altered proteolytic processing of OPA1 (optic atrophy 1). Scavenging mitochondrial ROS restored mitochondrial morphology in vivo and in vitro. CONCLUSIONS:Our results reveal a molecular mechanism by which lipid overload-induced mitochondrial ROS generation causes mitochondrial dysfunction by inducing post-translational modifications of mitochondrial proteins that regulate mitochondrial dynamics. These findings provide a novel mechanism for mitochondrial dysfunction in lipotoxic cardiomyopathy.

Dataset Information

Impaired OMA1-dependent cleavage of OPA1 and reduced DRP1 fission activity combine to prevent mitophagy in cells that are dependent on oxidative phosphorylation.

Publications

Impaired OMA1-dependent cleavage of OPA1 and reduced DRP1 fission activity combine to prevent mitophagy in cells that are dependent on oxidative phosphorylation.

Similar Datasets

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