Abstract
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.
Highlights
Prolonged cardiac hypertrophy in response to pathological stresses is the main risk factor for congestive heart failure, a leading cause of mortality and morbidity[1]
We demonstrate for the first time that cardiac expression of inhibitory factor 1 (IF1) is upregulated in pressure overload hearts
The loss of IF1 prevents excessive depolarization of the mitochondrial membrane and optimizes cardiac energy homeostasis with AMPK activation. These findings suggest a maladaptive response of IF1 upregulation in the chronically stressed heart
Summary
Prolonged cardiac hypertrophy in response to pathological stresses is the main risk factor for congestive heart failure, a leading cause of mortality and morbidity[1]. ATP synthase is a crucial protein complex in the mitochondria that couples osmo-chemical energy into ATP. Despite the well-recognized role of the ATP synthase in energy metabolism, the effect of changes in ATP synthase activities on cardiac pathogenesis remains obscure. The inhibitory factor 1 (IF1) is a nuclear-encoded ATP synthase interacting protein that suppresses the hydrolysis activity of ATP synthase[8, 9] under acidic conditions, such as in myocardial ischemia[10,11,12]. While IF1 knockout in mice leads to no overt phenotype[18], it remains unclear if IF1 in the in vivo heart becomes crucial in maintaining cardiac function under pathological stresses
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