Ultrastructural characterisation of the PINK1 mitophagy pathway using cryo-electron tomography

Mitochondria supply the cell with energy by generating ATP, but they are highly susceptible to damage. Mitophagy, the process by which damaged mitochondria are selectively degraded by the lysosome, ensures that cells maintain a healthy pool of mitochondria. The most well characterised mitophagy pathway is the PINK1/Parkin pathway. Upon mitochondrial damage, PINK1 is stabilised on the outer mitochondrial membrane, where it acts as both a sensor and effector to signal damage. Once stabilised, PINK1 dimerises and trans-autophosphorylates, rendering it active. PINK1 can then phosphorylate ubiquitin, generating a signal for the recruitment of the E3 ligase Parkin, which amplifies the mitochondrial ubiquitin signal to initiate mitophagy. Due to PINK1s key role in mitochondrial quality control, activating PINK1 is an attractive therapeutic strategy to enhance mitochondrial turnover in Parkinson’s disease. Resolving the structure of the double membrane spanning PINK1-TOM-TIM23 complex using cryo-electron tomography in situ in mitochondria will fully reveal how PINK1 is stabilised at the membrane and provide ground-breaking insights into the architecture of the TOM-TIM23 supercomplex. Callegari et al. Science 2025 doi 10.1126/science.adu6445 Gorelick et al. Journal of Structural Biology 2025 doi: 10.1016/j.jsb.2025.108249