Parker Alex M, Lees Jarmon G, Tate Mitchel, Phang Ren J, Velagic Anida, Deo Minh, Bishop Tayla, Krieg Thomas, Murphy Michael P, Lim Shiang Y, De Blasio Miles J, Ritchie Rebecca H
Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.
O'Brien Institute Department, St Vincent's Institute of Medical Research, Melbourne, VIC, Australia.
J Mol Cell Cardiol Plus. 2025 Jun 26;13:100469. doi: 10.1016/j.jmccpl.2025.100469. eCollection 2025 Sep.
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 Q 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.
活性氧（ROS）的过度产生和线粒体功能失调被认为是包括心力衰竭在内的心脏代谢疾病中心脏重塑进展的关键机制。传统治疗往往无效，因为它们没有特异性地针对潜在的病理机制。甲磺酸盐米托醌（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中的血管功能障碍。然而，MitoQ在限制氧化应激诱导的心肌细胞线粒体重塑方面的心脏保护潜力尚未完全明确。我们试图研究MitoQ及其线粒体靶向部分十二烷基三苯基鏻（dTPP）对过氧化氢诱导的H9C2大鼠心肌母细胞（H9C2-rCM）和人诱导多能干细胞衍生心肌细胞（hiPSC-CM）中ROS过度产生、线粒体功能失调和细胞死亡的影响。将心肌细胞暴露于载体对照（0.0001%超纯水）、过氧化氢（100μM）±MitoQ（1μM）或dTPP（1μM）对照的急性或慢性处理（5 - 60分钟或48小时）。MitoQ可显著减轻过氧化氢诱导的ROS过度产生、细胞外超氧化物、线粒体ROS、线粒体超极化和细胞死亡，但dTPP则不能，这表明在这些条件下MitoQ的辅酶Q部分具有保护作用。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表现出促进线粒体融合的作用。总体而言，我们的研究结果证实了MitoQ在限制氧化应激诱导的不良线粒体重塑和功能失调方面的细胞保护潜力，这种情况在心力衰竭中由心脏代谢诱导的心脏功能障碍中临床上可见。
