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Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission

Circulation research, 2018-01, Vol.122 (1), p.58-73 [Peer Reviewed Journal]

2018 American Heart Association, Inc. ;2017 American Heart Association, Inc. ;Copyright Lippincott Williams & Wilkins Ovid Technologies Jan 5, 2018 ;ISSN: 0009-7330 ;EISSN: 1524-4571 ;DOI: 10.1161/CIRCRESAHA.117.311307 ;PMID: 29092894

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Title:
Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission
Author: Tsushima, Kensuke ; Bugger, Heiko ; Wende, Adam R ; Soto, Jamie ; Jenson, Gregory A ; Tor, Austin R ; McGlauflin, Rose ; Kenny, Helena C ; Zhang, Yuan ; Souvenir, Rhonda ; Hu, Xiao X ; Sloan, Crystal L ; Pereira, Renata O ; Lira, Vitor A ; Spitzer, Kenneth W ; Sharp, Terry L ; Shoghi, Kooresh I ; Sparagna, Genevieve C ; Rog-Zielinska, Eva A ; Kohl, Peter ; Khalimonchuk, Oleh ; Schaffer, Jean E ; Abel, E Dale
Subjects: A Kinase Anchor Proteins - metabolism ; Adaptation ; Animals ; Animals, Newborn ; Atrophy ; Cardiomyocytes ; Cardiomyopathy ; Carnitine ; Cells, Cultured ; Diabetes mellitus ; Dynamin ; Dynamins - metabolism ; Electron transport ; Heart diseases ; Intermediates ; Isolated Heart Preparation - methods ; Kinases ; Lipids ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria ; Mitochondrial Dynamics - physiology ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Neonates ; Optic atrophy ; Optic Atrophy, Autosomal Dominant - metabolism ; Oxidation ; Oxidative stress ; Palmitic acid ; Phosphorylation ; Post-translation ; Protein Processing, Post-Translational - physiology ; Proteolysis ; Rats ; Rats, Wistar ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Rodents ; Transgenic mice ; Translation ; Ubiquitination ; Ventricle
Is Part Of: Circulation research, 2018-01, Vol.122 (1), p.58-73
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.
Publisher: United States: American Heart Association, Inc
Language: English
Identifier: ISSN: 0009-7330
EISSN: 1524-4571
DOI: 10.1161/CIRCRESAHA.117.311307
PMID: 29092894
Source: Geneva Foundation Free Medical Journals at publisher websites
MEDLINE

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Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission

2018 American Heart Association, Inc. ;2017 American Heart Association, Inc. ;Copyright Lippincott Williams & Wilkins Ovid Technologies Jan 5, 2018 ;ISSN: 0009-7330 ;EISSN: 1524-4571 ;DOI: 10.1161/CIRCRESAHA.117.311307 ;PMID: 29092894

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