MitoQ Protects Against Oxidative Stress-Induced Mitochondrial Dysregulation in Human Cardiomyocytes

Alex M. Parker , Jarmon G. Lees , Mitchel Tate , Ren J. Phang , Anida Velagic , Minh Deo , Tayla Bishop , Thomas Krieg , Michael P. Murphy , Shiang Y. Lim , Miles J. De Blasio , Rebecca H. Ritchie
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Abstract

The overproduction of reactive oxygen species (ROS) and mitochondrial dysregulation are regarded as key mechanisms in the progression of cardiac remodelling in cardiometabolic diseases including heart failure. Conventional treatments are often ineffective as they do not specifically target the underlying pathological mechanisms. Mitoquinone mesylate (MitoQ), a mitochondrial-targeted antioxidant has been reported to be protective against vascular dysfunction in hypertension, diabetic kidney disease and alcohol-induced liver damage. However, the cardioprotective potential of MitoQ to limit oxidative stress-induced mitochondrial remodelling in cardiomyocytes has not been fully resolved. We sought to investigate the effect of MitoQ and its mitochondrial-targeting moiety dodecyl-triphenylphosphonium (dTPP) on hydrogen peroxide-induced overproduction of ROS, mitochondrial dysregulation and cell death in H9C2 rat cardiomyoblasts (H9C2-rCM) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Cardiomyocytes were exposed to acute or chronic treatment (5–60 min or 48 h) of vehicle control (0.0001 % Ultrapure Milli-Q water), hydrogen peroxide (100 μM) ± MitoQ (1 μM) or dTPP (1 μM) control. Hydrogen peroxide-induced overproduction of ROS, extracellular superoxide, mitochondrial ROS, mitochondrial hyperpolarisation and cell death were significantly blunted by MitoQ, but not dTPP, suggesting that the coenzyme Q10 moiety of MitoQ is protective under these conditions. Interestingly, both MitoQ and dTPP exhibited a pro-mitochondrial fusion effect by preserving mitochondrial network and reducing mitochondrial fragmentation in oxidative stress conditions. Overall, our findings confirm the cytoprotective potential of MitoQ to limit oxidative stress-induced adverse mitochondrial remodelling and dysregulation that is clinically observed in cardiometabolic-induced cardiac dysfunction in the failing heart.

Abstract Image

MitoQ保护心肌细胞免受氧化应激诱导的线粒体失调
活性氧(ROS)的过量产生和线粒体失调被认为是心脏代谢疾病(包括心力衰竭)中心脏重构进展的关键机制。常规治疗往往是无效的,因为他们没有专门针对潜在的病理机制。甲磺酸米托醌(Mitoquinone mesylate, MitoQ)是一种线粒体靶向抗氧化剂,据报道可预防高血压、糖尿病肾病和酒精性肝损伤的血管功能障碍。然而,MitoQ限制心肌细胞氧化应激诱导的线粒体重构的心脏保护潜力尚未完全解决。我们试图研究MitoQ及其线粒体靶向片段十二烷基三苯磷(dTPP)对H9C2大鼠成心肌细胞(H9C2- rcm)和人诱导多能干细胞源性心肌细胞(hiPSC-CM)过氧化氢诱导的ROS过量产生、线粒体失调和细胞死亡的影响。心肌细胞暴露于急性或慢性对照(5-60分钟或48小时)的对照剂(0.0001 %超纯milliq水)、过氧化氢(100 μM)±MitoQ (1 μM)或dTPP (1 μM)。过氧化氢诱导的ROS过量产生、细胞外超氧化物、线粒体ROS、线粒体超极化和细胞死亡被MitoQ显著减弱,但dTPP没有,这表明MitoQ的辅酶Q10片段在这些条件下具有保护作用。有趣的是,在氧化应激条件下,MitoQ和dTPP都通过保留线粒体网络和减少线粒体碎片化而表现出促进线粒体融合的作用。总的来说,我们的研究结果证实了MitoQ的细胞保护潜力,以限制氧化应激诱导的不良线粒体重构和失调,这在临床上观察到心脏衰竭时心脏代谢诱导的心功能障碍。
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来源期刊
Journal of molecular and cellular cardiology plus
Journal of molecular and cellular cardiology plus Cardiology and Cardiovascular Medicine
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