Figure 7.

Mitochondrial clearance via the ubiquitin-mediated pathway. Upon mitochondrial depolarization, a cascade of events is initiated, which targets damaged mitochondria, or portions of it, for degradation by the autophagy machinery. In a first step, the kinase PINK1 accumulates at the mitochondrial outer membrane and initiates phosphorylation (P) and recruitment of the E3 ligase Parkin. Activated Parkin ubiquitylates (U) several outer mitochondrial membrane proteins such as Mitofusins 1 and 2. Additional phosphorylation of ubiquitin generates a positive feedback loop increasing Parkin recruitment and further ubiquitylation. The formation of ubiquitin chains on mitochondrial surface proteins promotes its binding to lipidated LC3, an autophagosome receptor, via the mitochondrial receptors (R) such as optineurin, NDP52, or p62. From this point, the mitochondria, or its fragments, meant to be degraded are surrounded by the autophagosome, which finally fuses with the lysosome for final destruction.