Fig. 3

PINK1/PARKIN-directed quality control in damaged mitochondria. After damage, PINK1 is no longer imported into the inner mitochondrial membrane (IMM) and accumulates on the outer mitochondrial membrane (OMM). Here, a supercomplex composed by TOM complex subunits and PINK1 homodimers is formed, facilitating PINK1 autophosphorylation and activation. Once activated, PINK1 phosphorylates ubiquitinated substrates on the OMM and PARKIN enable its E3 ubiquitin ligase functions in concert with E2 ubiquitin-conjugating enzymes. PINK1-mediated phosphorylation of ubiquitin phospho-Ser65- ubiquitin on OMM substrates acts as the PARKIN receptor for its recruitment from the cytosol. PINK1 and PARKIN initiate a positive feedback loop, resulting in the coating of damaged mitochondria with phospho-ubiquitin chains. Individual OMM proteins decorated with poly-ubiquitin can be extracted from the membrane and degraded by the 26 S proteasome. Phospho-ubiquitin chains are bound by two mitophagy adaptors, nuclear domain 10 protein 52 (NDP52) and optineurin. Phosphorylation of optineurin by TANK Binding Kinase 1 (TBK1) enhances its binding to ubiquitin chains and promotes selective autophagy of damaged mitochondria. The two adaptors recruit autophagosomes via microtubule-associated protein 1A/1B-light chain 3 (LC3) binding, allowing the engulfment of dysfunctional mitochondria resulting in their direct degradation in lysosome