Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA.
Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
Sci Rep. 2017 Sep 5;7(1):10501. doi: 10.1038/s41598-017-11251-8.
Mitochondrial ATP synthase catalyzes the coupling of oxidative phosphorylation. Under pathological conditions, ATP synthase hydrolyzes ATP to replenish protons from the matrix into the intermembrane space, sustaining mitochondrial membrane potential. ATPase inhibitory factor 1 (IF1) is a nuclear-encoded, ATP synthase-interacting protein that selectively inhibits the hydrolysis activity of ATP synthase, which may render the protective role of IF1 in ischemic hearts. However, the in vivo cardiac function of IF1 and the potential therapeutic application targeting IF1 remain obscure. In the present study, we uncovered that IF1 is upregulated in mouse hearts with pressure overload-induced hypertrophy and in human hearts with dilated cardiomyopathy. IF1 knockout (KO) mice were protected against cardiac dysfunction and pathological development induced by transverse aortic constriction (TAC) or isoproterenol infusion. The reduced ATP hydrolysis activated AMPK activity in IF1 KO hearts, which together facilitated autophagy. These results suggest that IF1 upregulation in the failing heart may be a maladaptive response. Inhibiting IF1 in the hypertrophied heart not only prevents cell death from excessive mitochondrial depolarization but also activates AMPK signaling and increases autophagy. Therefore, IF1 inhibition may serve as a potential therapeutic target in treating pathological cardiac hypertrophy and heart failure.
线粒体 ATP 合酶催化氧化磷酸化的偶联。在病理条件下，ATP 合酶将 ATP 水解以从基质中补充质子到膜间空间，维持线粒体膜电位。ATP 酶抑制因子 1（IF1）是一种核编码的、与 ATP 合酶相互作用的蛋白，它选择性地抑制 ATP 合酶的水解活性，这可能使 IF1 在缺血性心脏中发挥保护作用。然而，IF1 的体内心脏功能以及针对 IF1 的潜在治疗应用仍然不清楚。在本研究中，我们发现 IF1 在压力超负荷诱导的肥厚小鼠心脏和扩张型心肌病患者心脏中上调。IF1 敲除（KO）小鼠对由横主动脉缩窄（TAC）或异丙肾上腺素输注诱导的心脏功能障碍和病理性发展有保护作用。IF1 KO 心脏中减少的 ATP 水解激活了 AMPK 活性，这共同促进了自噬。这些结果表明，衰竭心脏中 IF1 的上调可能是一种适应不良的反应。在肥大心脏中抑制 IF1 不仅可以防止过度的线粒体去极化引起的细胞死亡，还可以激活 AMPK 信号通路并增加自噬。因此，IF1 抑制可能成为治疗病理性心肌肥厚和心力衰竭的潜在治疗靶点。
