Ablation of the stress protease OMA1 protects against heart failure in mice

Loss of OMA1 protects cardiomyocytes from death in three murine models of heart failure with diverse etiologies. A mitochondrial mark for heart failure Current therapies for heart failure vary depending on the root cause and stage of the disease. Acin-Perez et al. studied the molecular link between mitochondrial dysfunction and heart failure, focusing on OMA1, a protease involved in mitochondrial inner membrane remodeling and cytochrome c release. Using three mouse models of heart failure, they found that cardiomyocytes were protected from mitochondrial reactive oxygen species–induced cell death when OMA1 was ablated. OMA1 could be a therapeutic target for heart failure. Heart failure (HF) is a major health and economic burden in developed countries. It has been proposed that the pathogenesis of HF may involve the action of mitochondria. We evaluate three different mouse models of HF: tachycardiomyopathy, HF with preserved left ventricular (LV) ejection fraction (LVEF), and LV myocardial ischemia and hypertrophy. Regardless of whether LVEF is preserved, our results indicate that the three models share common features: an increase in mitochondrial reactive oxygen species followed by ultrastructural alterations in the mitochondrial cristae and loss of mitochondrial integrity that lead to cardiomyocyte death. We show that the ablation of the mitochondrial protease OMA1 averts cardiomyocyte death in all three murine HF models, and thus loss of OMA1 plays a direct role in cardiomyocyte protection. This finding identifies OMA1 as a potential target for preventing the progression of myocardial damage in HF associated with a variety of etiologies.