Molecular diversity of mitochondrial autophagy receptors: context-dependent effects in human health and disease

Mitophagy receptors are central regulators of mitochondrial quality control, integrating metabolic, stress-related, and developmental cues to maintain cellular homeostasis. Accumulating evidence indicates that their dysregulation contributes to a broad spectrum of human diseases through highly context-dependent mechanisms. In cardiovascular and neurological disorders, receptor-mediated mitophagy shapes cell survival, synaptic function, stress adaptation, and tissue integrity, with both insufficient and excessive activity proving detrimental. In cancer, mitophagy receptors display dual and stage-specific roles, acting as tumor suppressors in early disease while later supporting metabolic adaptation, stemness, and therapy resistance. Metabolic diseases highlight the tissue-specific complexity of mitophagy regulation, where precise control of mitochondrial turnover is essential for insulin sensitivity, calcium signaling, and energy homeostasis. In hematological, inflammatory, and autoimmune disorders, receptor-mediated mitophagy emerges as a fundamental determinant of lineage commitment, immune cell function, and inflammatory balance. Collectively, these findings position mitophagy receptors not as uniform stress responders, but as dynamic modulators of disease progression, whose precise and context-sensitive targeting may offer novel therapeutic opportunities across diverse pathological conditions.