线粒体分裂
脂毒性
线粒体
生物
细胞生物学
线粒体ROS
活性氧
线粒体融合
DNAJA3公司
DNM1L型
ATP-ADP转位酶
第一季
内科学
线粒体DNA
生物化学
内分泌学
线粒体内膜
医学
胰岛素抵抗
胰岛素
基因
作者
Kensuke Tsushima,Heiko Bugger,Adam R. Wende,Jamie Soto,Gregory A. Jenson,Austin R. Tor,Rose McGlauflin,Helena Kenny,Yuan Zhang,Rhonda Souvenir,Xiao Xuan Hu,Crystal Sloan,Renata O. Pereira,Vitor A. Lira,Kenneth W. Spitzer,Terry L. Sharp,Kooresh I. Shoghi,Genevieve C. Sparagna,Eva A. Rog-Zielinska,Peter Kohl,Oleh Khalimonchuk,Jean E. Schaffer
出处
期刊:Circulation Research
[Ovid Technologies (Wolters Kluwer)]
日期:2018-01-05
卷期号:122 (1): 58-73
被引量:225
标识
DOI:10.1161/circresaha.117.311307
摘要
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.To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo.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.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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