Fig. 6. Regulation of PINK1/Parkin-mediated mitophagy by TFEB.

In the case of mitochondria damage and loss of membrane potential, PINK1 is recruited to the OMM and activated through auto-phosphorylation. PINK1 triggers mitophagy initiation by phosphorylating the ubiquitin attached to the damaged and misfolded OMM proteins. Simultaneously, PINK1 also phosphorylates Parkin, an E3 ligase, causing its activation. Activated Parkin further amplifies the signal by further ubiquitinating misfolded OMM proteins. In addition, phosphorylated ubiquitin also recruits autophagy receptors (blue) to induce autophagosome formation, for degradation of damaged mitochondria. This process requires the transcriptional activity of nuclear TFEB to induce the expression of genes involved in autophagy biogenesis. Additionally, ATG5 activates TFEB via an unknown mechanism, while TFEB nuclear localization is Parkin-dependent. TFEB also induces the expression of PGC1α, a master regulator of mitochondrial biogenesis.