Deubiquitinases in mitophagy: therapeutic control of mitochondrial quality.

Mitochondrial quality control is essential for maintaining cellular and tissue homeostasis. Mitophagy, the selective autophagic removal of damaged mitochondria, is a central component of this process, and defects in mitophagy are increasingly linked to neurodegeneration, cardiovascular disease, cancer, and inherited mitochondrial disorders. Ubiquitin-dependent tagging of outer mitochondrial membrane proteins is a major mechanism for marking damaged mitochondria for clearance; however, recent advances reveal that mitochondrial deubiquitinases (DUBs) shape ubiquitin signaling at damaged mitochondria, thereby influencing the efficiency and selectivity of mitochondrial turnover. Moreover, DUBs are emerging as context-dependent editors of the mitochondrial ubiquitin code that link mitophagy to disease pathogenesis and therapeutic intervention. Here, we synthesize current understanding of mitochondrial DUBs in physiology and disease and discuss emerging pharmacological strategies to guide the development of mitophagy-targeted therapeutics.