BACKGROUND AND OBJECTIVE: Mitochondria generate nearly 90% of cellular adenosine triphosphate (ATP) and are essential for maintaining cardiac energetic homeostasis. Mitophagy, a selective autophagic process that removes damaged mitochondria, is critical for preserving mitochondrial quality and ensuring cardiomyocyte survival under stress. Given that cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide and are profoundly influenced by mitochondrial dysfunction, understanding mitophagy has become increasingly important. This review aims to summarize the current mechanistic findings related to mitophagy, examine its roles across major CVDs, and evaluate emerging mitophagy-targeted interventions with potential clinical application.
METHODS: A comprehensive literature search of PubMed was conducted using keywords, including "mitophagy", "cardiovascular disease", "myocardial ischemia-reperfusion", to retrieve relevant studies published in English between January 2020 and March 2025. Original studies, reviews, and clinically relevant reports were included in the literature review to ensure broad coverage of mechanistic and translational findings.
KEY CONTENT AND FINDINGS: The review synthesizes current knowledge on canonical and noncanonical mitophagy pathways, as well as their roles in myocardial ischemia-reperfusion injury, heart failure, cardiomyopathies, and metabolic cardiomyopathy. Recent evidence highlights the dual nature of mitophagy, where both insufficient and excessive activation impair cardiac function. The review further discusses innovative therapeutic strategies, including mitochondrial-targeted nanoparticles, small-molecule mitophagy activators, and exercise-induced mitochondrial remodeling, along with their potential benefits and limitations. Key knowledge gaps have been identified, including the tissue-specific regulation of mitophagy and uncertainties surrounding dose-dependent therapeutic activation.
CONCLUSIONS: Mitophagy is a pivotal determinant of mitochondrial homeostasis and cardiac health. While emerging interventions show promise, precise modulation remains challenging. Advancing quantitative assessment tools, defining safe activation thresholds, and developing cell-type-specific targeting strategies will be essential for clinical translation. This review provides a comprehensive framework that may guide future research and inform the development of mitophagy-based therapies for CVDs.
