Figure 4. The mechanism of mitophagy.

Mammalian mitophagy is believed to occur through at least two pathways, programmed mitophagy and selective mitophagy, although significant cross talk between these has been found. Programmed mitophagy was discovered in maturing red blood cells through upregulation of the protein NIX that may facilitate the dissociation of the anti-mitophagic proteins Bcl-2 and Bcl-XL from the pro-mitophagic protein Beclin-1. This potentially derepresses Beclin-1 allowing recruitment of the Vps34-15-AMBRA complex that in turn will associate with the autophagosome elongation machinery atg5-12/atg16 leading to the formation of an autophagosome. NIX coats the mitochondria and associates directly with LC3 which binds to the growing autophagosome. Mitophagy is completed by the fusion of the mitophagosome with a lysosome. In selective mitophagy the initiating event is believed to be mitochondrial inner membrane depolarization leading to PINK1 accumulation at the outer membrane. PINK1 phosphorylates Parkin, Mfn2 and other proteins leading to the activation of Parkin. Parkin is a E3-ubiquitin ligase that upon activation ubiquitinates outer mitochondrial membrane proteins (OMPs), possibly VDAC, are ubiquitinated. Vps34-15-AMBRA complex and the Atg5-12/atg16 complex is recruited by activated PINK1/Parkin. Outer membrane ubiquitination leads to the recruitment of p62 which will associate with LC3 on the growing autophagosome. When the autophagosome is completed, fusion with a lysosome will lead to complete degradation of the mitochondria.