氧化还原信号和心脏功能紧密相关。然而，在很大程度上未知的是哪些蛋白质靶标受到心肌细胞中过氧化氢 (H 2 O 2 ) 的影响，这在氧化应激过程中会削弱正性肌力作用。在这里，我们结合化学遗传学小鼠模型（HyPer-DAO 小鼠）和氧化还原蛋白质组学方法来识别氧化还原敏感蛋白。使用 HyPer-DAO 小鼠，我们证明内源性 H 2 O 2产量增加在心肌细胞中导致体内心肌收缩力的可逆损伤。值得注意的是，我们将 TCA 循环酶异柠檬酸脱氢酶 (IDH)3 的 γ 亚基鉴定为氧化还原开关，将其修饰与改变的线粒体代谢联系起来。使用微秒分子动力学模拟和使用半胱氨酸基因编辑细胞的实验表明，IDH3γ Cys148 和 284 关键参与IDH3 活性的H 2 O 2依赖性调节。我们的发现提供了一种意想不到的机制，通过该机制可以通过氧化还原信号过程调节线粒体代谢。

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Redox signaling and cardiac function are tightly linked. However, it is largely unknown which protein targets are affected by hydrogen peroxide (H2O2) in cardiomyocytes that underly impaired inotropic effects during oxidative stress. Here, we combine a chemogenetic mouse model (HyPer-DAO mice) and a redox-proteomics approach to identify redox sensitive proteins. Using the HyPer-DAO mice, we demonstrate that increased endogenous production of H2O2 in cardiomyocytes leads to a reversible impairment of cardiac contractility in vivo. Notably, we identify the γ-subunit of the TCA cycle enzyme isocitrate dehydrogenase (IDH)3 as a redox switch, linking its modification to altered mitochondrial metabolism. Using microsecond molecular dynamics simulations and experiments using cysteine-gene-edited cells reveal that IDH3γ Cys148 and 284 are critically involved in the H2O2-dependent regulation of IDH3 activity. Our findings provide an unexpected mechanism by which mitochondrial metabolism can be modulated through redox signaling processes.