Figure 7. Model for Parkin‐mediated inhibition of intrinsic apoptosis.

Model of the effect of Parkin‐mediated BAK ubiquitination on intrinsic apoptosis. Following mitochondrial damage, PINK1 is stabilised at the mitochondrial outer membrane (MOM) whereby it phosphorylates ubiquitin to recruit Parkin. Phosphorylation by PINK1 activates Parkin to ubiquitinate a variety of substrates including Mfn2 and VDAC. Parkin ubiquitinates BAK on a conserved lysine (K113) to inhibit BAK oligomerisation and its apoptotic function in releasing cytochrome c from the inter‐membrane space (IMS). Additionally, Parkin ubiquitinates VDAC2, that we propose limits BAX association with mitochondria. This limits apoptosis mediated by both BAK and BAX, thus enabling the effective engulfment of the mitochondrion by the autophagosome without errant activation of apoptosis.