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

Authors

Kensuke Tsushima, University of Iowa
Heiko Bugger, University of Utah School of MedicineFollow
Adam R. Wende, University of Utah School of MedicineFollow
Jamie Soto, University of IowaFollow
Gregory A. Jenson, University of IowaFollow
Austin R. Tor, University of IowaFollow
Rose McGlauflin, University of IowaFollow
Helena C. Kenny, University of IowaFollow
Yuan Zhang, University of IowaFollow
Rhonda Souvenir, University of IowaFollow
Xiao X. Hu, University of Utah School of Medicine
Crystal L. Sloan, University of Utah School of Medicine
Renata O. Pereira, University of IowaFollow
Vitor A. Lira, University of IowaFollow
Kenneth W. Spitzer, University of Utah School of MedicineFollow
Terry L. Sharp, Washington University School of MedicineFollow
Kooresh I. Shoghi, Washington University School of MedicineFollow
Genevieve C. Sparagna, University of Colorado Anschutz Medical CenterFollow
Eva A. Rog-Zielinska, University of Freiburg
Peter Kohl, University of FreiburgFollow
Oleh Khalimonchuk, University of Nebraska-LincolnFollow
Jean E. Schaffer, Washington University School of MedicineFollow
E. Dale Abel, University of IowaFollow

Document Type

Article

Date of this Version

11-1-2017

Citation

Published in Circulation Research (2017), doi: 10.1161/CIRCRESAHA.117.311307

Comments

Copyright © 2017 American Heart Association. Used by permission.

Abstract

Rationale: Cardiac lipotoxicity, characterized by increased uptake, oxidation and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes. 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 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 (NRVCs). Palmitate exposure to NRVCs initially activates mitochondrial respiration, coupled with increased mitochondrial membrane potential and adenosine triphosphate (ATP) synthesis. However, long-term exposure to palmitate (>8h) 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 A-kinase anchor protein (AKAP121) leading to reduced phosphorylation of DRP1 at Ser637 and altered proteolytic processing of OPA1. 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.

38 pp; includes supplemental materials.