FUNDC1-Mediated Mitophagy in Cardiovascular Disease: Context-Dependent Regulation of Mitochondrial Quality Control and Dysfunction

Mitochondrial quality-control failure contributes to cardiovascular injury, but the consequences of mitophagy depend on the nature and timing of stress. FUN14 domain-containing protein 1 (FUNDC1) is an outer mitochondrial membrane mitophagy receptor that also regulates mitochondrial dynamics, mitochondria–endoplasmic reticulum contacts, and Ca 2 ⁺ homeostasis. This review synthesizes the regulation of FUNDC1 and critically examines its context-dependent effects in myocardial ischemia/reperfusion injury (MIRI), heart failure and myocardial remodeling, and metabolic cardiomyopathy. In several MIRI and heart-failure models, impaired FUNDC1-associated mitochondrial quality control is linked to injury, whereas excessive or mistimed FUNDC1-associated mitophagy may be detrimental in selected reperfusion and pulmonary vascular settings. In metabolic cardiomyopathy, hyperglycemia-associated FUNDC1–IP3R2 signaling promotes abnormal organelle contacts and mitochondrial Ca 2 ⁺ overload, whereas FUNDC1 deficiency during lipid overload is linked to mitochondrial damage and heightened lipotoxic susceptibility. These apparently divergent effects may reflect differences in cellular context, stress exposure, disease stage, and mitophagy-independent FUNDC1 functions; however, the underlying causal mechanisms remain incompletely defined. We highlight inconsistencies among experimental models and distinguish evidence from direct mitophagy-flux measurements from conclusions based on indirect markers. Given the predominance of preclinical evidence, further mechanistic and translational studies are needed before FUNDC1-directed therapies can be considered for clinical use.