The pathways of mitophagy for quality control and clearance of mitochondria

Abstract

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.

Figure 1

Three major pathways of mitochondrial quality control. Misfolded mitochondrial membrane proteins can be degraded by two AAA protease complexes with catalytic sites facing both sides of the inner membrane. Mitochondrial proteins can also be degraded by being transferred to lysosomes; vesicles budding from mitochondrial tubules sequester selected mitochondrial cargos, and deliver those mitochondrial components to the lysosome for degradation. The third pathway, known as mitophagy, involves sequestration of an entire mitochondrion within a double-membrane vesicle, the autophagosome, followed by fusion with a lysosome

Figure 2

From mitochondrial network to fragmentation and mitophagy. Mitochondria typically form an interconnected network, but fission events and a block of fusion can fragment the network and thereby segregate a mitochondrion destined for mitophagy from the rest of the network. An isolation membrane, of an unknown origin, forms around this mitochondrial fragment. Closure of the isolation membrane, with the help of LC3/ATG8, gives rise to an autophagosome engulfing the mitochondrion. The autophagosome fuses with the lysosome forming an autolysosome in which the mitochondrial cargo is degraded

Figure 3

Pathways of mitophagy. (a) Damaged mitochondria that have lost their membrane potential (ψm) are eliminated by mitophagy through the accumulation of PINK1 and the E3 ubiquitin ligase Parkin on the mitochondrial surface. (b) In developing reticulocytes, all mitochondria are eliminated by mitophagy. The mitochondrial outer membrane protein, Nix, may serve as a receptor for targeting mitochondria to autophagosomes. (c) Sperm-derived mitochondria are selectively eliminated from fertilized oocytes through mitophagy, thereby allowing for exclusively maternal inheritance of mitochondrial DNA

Figure 4

The PINK1/Parkin pathway of mitophagy. (a) In healthy mitochondria, PINK1 is imported to the inner mitochondrial membrane, presumably through the TOM/TIM complex. The TIM complex-associated protease, mitochondrial MPP, cleaves PINK1 mitochondrial targeting sequence (MTS). PINK1 is also cleaved by the inner membrane presenilin-associated rhomboid-like protease PARL and ultimately proteolytically degraded. Loss of membrane potential in damaged mitochondria prevents the import of PINK1 leading to the accumulation of unprocessed PINK1 on the outer membrane surface where it associates with the TOM complex, and recruits cytosolic Parkin, via an unknown mechanism, to damaged mitochondria. (b) Parkin promotes mitophagy of damaged mitochondria in two major ways. (i) In one mechanism, Parkin, presumably through its ubiquitin–ligase activity, causes the degradation of its substrates such as Miro and Mitofusin. In the case of Miro, its phosphorylation by PINK1 is upstream of the Parkin-dependent proteosomal degradation. Mitocondrial fragmentation and arrest of motility, through loss of Mitofusin and Miro, quarantine damaged mitochondria and promote their autophagosomal engulfment. (ii) Alternatively or in addition, Parkin-mediated hyper-ubiquitination of the mitochondrial outer membrane is recognized by ubiquitin-binding adaptors, such as p62, HDAC6, and unknown others, that may recruit damaged mitochondria to the isolation membrane through their interaction with the autophagosomal protein LC3