Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induces
Post-Translational Modifications of AKAP121, DRP1 and OPA1 That Promote
Mitochondrial Fission.
Authors Tsushima K, Bugger H, Wende AR, Soto J, Jenson GA, Tor AR, McGlauflin R, Kenny
HC, Zhang Y, Souvenir R, Hu XX, Black CL, Pereira RO, Lira VA, Spitzer K, Sharp
TL, Shoghi KI, Sparagna GC, Rog-Zielinska EA, Kohl P, Khalimonchuk O, Schaffer
JE, Abel ED
Submitted By Junguk Hur on 11/21/2017
Status Published
Journal Circulation research
Year 2017
Date Published 11/1/2017
Volume : Pages Not Specified : Not Specified
PubMed Reference 29092894
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.

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