Mastering cardiomyocyte mitophagy: molecular governance, pathological derailment and therapeutics

Mitophagy is a pivotal quality control pathway that maintains cardiac energy metabolism and structural stability by selectively removing damaged or senescent mitochondria, thereby keeping mitochondrial dynamics in balance. This process secures cardiomyocyte survival, calcium handling, and contractile function during both rest and stress. When mitophagic flux is inadequate, accumulation of reactive oxygen species, disruption of calcium homeostasis, and uncontrolled inflammation act together to drive pathological hypertrophy, heart failure, cardiac aging, and obesity-associated cardiomyopathy. Conversely, appropriate activation of mitophagy can lessen structural injury and restore pump performance during ischemia reperfusion, pressure overload, and metabolic stress. This review summarizes the central regulatory network of cardiac mitophagy and its pathological roles across cardiovascular disorders, emphasizing that careful modulation of flux is essential for preserving myocardial homeostasis. Recent experimental strategies that target mitophagy are also discussed, providing a theoretical foundation for the development of precise cardioprotective therapies.