Fig. 2

PINK1-Parkin‐mediated mitophagy. With the help of TOM22 and TOM70, TOM20 recognizes the MTS sequence and guides PINK1 into the translocation pore formed by TOM40, which transfers PINK1 to the TIM23 complex in the IMM. Then, PINK1 is sequentially cleaved by the MPP and the PARL, followed by the N-terminal regular degradation pathway. PHB2 binds to PARL to prevent it from directly processing PINK1 in the IMM. When mitochondria are damaged (e.g., depolarization of the mitochondrial membrane), the ANT complex inhibits the translocation of PINK1 to TIM23 via interaction with TIM44. Meanwhile, CTE interaction in PINK1 binds to TOM7, resulting in the stabilization of PINK1 on the OMM. Then, PINK1 undergoes trans-autophosphorylation. Monomeric PINK1 phosphorylates Ub, and then pUb binds RING1 to release Ubl. The Ubl is phosphorylated by PINK1, resulting in the release of the RING2 and exposure of the E2 interaction surface in the RING1. The RING2 then receives ubiquitin from E2 via a thioester linkage and transfers it to the substrate. Parkin is activated to ubiquitinate a number of OMM proteins. These ubiquitin proteins are further phosphorylated by PINK1, which recruits more Parkin to mitochondria and thus generates more ubiquitin chains. Finally, ubiquitin chains on mitochondria are recognized by autophagic adapters (P62, NBR1, NDP52/CALCOCO2, TAX1BP1, and OPTN), leading to mitophagy. RABGEF1 can be recruited to damaged mitochondria via binding to the downstream of Parkin by ubiquitination, which then directs the downstream Rab5 and Rab7 to the damaged mitochondria. Recruited Rab7 promotes Atg9-mediated vesicle assembly and LC3-labeled autophagy membrane encapsulation