Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration. Facts Mitophagy mediates clearance of damaged mitochondria, and is also involved in the removal of mitochondria from maturing erythrocytes and eliminating sperm-derived mitochondria after fertilization. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the core autophagic machinery to mitochondria for their selective removal. A pathway containing PTEN-induced putative protein kinase 1 (PINK1) and Parkin responds to loss of mitochondrial membrane potential by targeting damaged mitochondria for clearance. The PINK1/Parkin pathway is triggered when PINK1 is stabilized on the outer membrane of damaged mitochondria, where it facilitates recruitment of cytosolic Parkin. Damaged mitochondria are prevented from moving and fusing with the mitochondrial reticulum in preparation for their mitophagic clearance.
Open QuestionsHow distinct are the mitophagy pathways triggered by different stimuli or conditions?To what extent does Parkin activate mitophagy by causing the degradation of mitochondrial surface proteins or hyperubiquitinating the mitochondrial surface? How do PINK1 and Parkin interact with one another and with substrates on the mitochondrial surface in causing mitophagy? In contrast to the remarkable conservation of the core autophagic machinery, why are mitophagy-specific genes so little conserved between yeast and mammals? How best should mitophagy be triggered by researchers probing physiologically relevant pathways?The mitochondrion is an important actor in the life of a eukaryotic cell, but, like all good actors, a mitochondrion needs to exit the stage at the right time. Mitophagy removes mitochondria once they have played their part. This artic...