Mitophagy: a complex mechanism of mitochondrial removal.

SIGNIFICANCE: Mitochondrial dynamics and turnover are crucial for cellular homeostasis and differentiation. The removal of damaged mitochondria that could contribute to cellular dysfunction or death is achieved through the process of mitochondrial autophagy, i.e., mitophagy. Moreover, mitophagy is responsible for removal of mitochondria during terminal differentiation of red blood cells and T cells. RECENT ADVANCES: Recent work is elucidating how mitochondria are recognized for selective mitophagy either by PINK1 and Parkin or mitophagic receptors Nix and Bnip3 and their accompanying modulators. PINK1/Parkin-mediated mitophagy reveals their role of cargo recognition through polyubiquitination of mitochondrial proteins, while Nix functions as a regulated mitophagy receptor. These recognized modes of capture by the autophagy machinery operate at different efficiencies, from partial to complete elimination of mitochondria. CRITICAL ISSUES: It is critical to understand that the distinct regulatory mechanisms involve not only autophagy machinery, but also proteins associated with mitochondrial fusion and fission and therefore, regulation of mitochondrial morphology. The end result is either finely tuned quality control of damaged mitochondria, or mitochondrial clearance during development- induced mitophagy. FUTURE DIRECTIONS: In this article, known mechanisms and future directions for deciphering the challenge of mitophagy regulation will be discussed.