The TBK1-OPTN Axis Mediates Crosstalk Between Mitophagy and the Innate Immune Response: A Potential Therapeutic Target for Neurodegenerative Diseases

TBK1-OPTN axis facilitates the turnover of impaired mitochondria via mitophagy. Step 1. Mitochondrial damage leads to depolarization induced by the uncoupler carbonyl-cyanide m-chlorophenyl-hydrazine. Step 2. Accumulation of PINK1 (PTEN-induced putative kinase 1) recruits the E3 ubiquitin ligase parkin, contributing to the ubiquitination of outer mitochondrial membrane proteins. Step 3. PINK1-parkin activation promotes TBK1 phosphorylation of S172 on mitochondria. TBK1 phosphorylates OPTN at Ser177, Ser473, and Ser513, thereby enhancing the capacity of OPTN to bind to poly-Ub chains. In turn, poly-Ub chain binding to OPTN is required for TBK1 recruitment and activation on mitochondria. Step 4. Thus, the TBK1-OPTN axis promotes autophagosome formation around damaged mitochondria via the LC3-interacting domain (LIR) and is sufficient for mitophagy