Mitochondrial protein OPA3 sustains cardiac function by regulating calcium handling in male mice.

Heart failure (HF) is a growing global health burden characterized by impaired cardiac contractility and progressive remodeling, driven in part by disrupted Ca2+ handling and mitochondrial dysfunction. However, the molecular mechanisms coordinating these processes remain incompletely understood. Here we showed that OPA3 was decreased in both human and murine HF. Cardiomyocyte-specific deletion of Opa3 in male mice led to the progressive dilated cardiomyopathy (DCM), accompanied by impaired myocardial function, calcium cycling and mitochondria function. Mechanistically, OPA3 forms multimers that are required for its interaction with phospholamban (PLN), thereby maintaining sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) activity and Ca2+ handling. OPA3 is localized to the mitochondrial outer membrane, and its absence impaired mitochondrial function. Cardiomyocyte-specific overexpression of Opa3 improved cardiac dysfunction in both pressure overload- and doxorubicin-induced HF models. Our data define a critical role of OPA3-PLN-SERCA2a axis that regulates both mitochondria and SR function, representing a potential therapeutic target for HF.