J. Cell Biol. 216, 3231–3247 (2017)

Protein aggregation within the mitochondrial matrix promotes Parkin recruitment and PINK1–Parkin-dependent mitophagy. Yet how Parkin mediates selective autophagic elimination of misfolded proteins localized to mitochondria, and the role of mitochondrial fission in mitophagy, have remained unclear.

Youle and colleagues report that PINK1 recruits Parkin to focal sites on mitochondria harbouring misfolded protein aggregates, and that mitochondrial fission protects undamaged mitochondria from elimination.

Using a system to visualize misfolded aggregates of mitochondrial-localized mutant ornithine transcarbamylase (ΔOTC), the authors showed that PINK1 recruited cytosolic Parkin to focal spots on mitochondria that were proximal to ΔOTC. Induction of mitochondrial misfolding also caused PINK1-dependent Parkin recruitment to polarized mitochondrial subdomains. Autophagy receptors and LC3 were recruited to Parkin foci in ΔOTC-expressing cells and co-localized with ΔOTC in a PINK1-dependent manner. The authors found that mitochondrial fission factor Drp1 recruitment to Parkin foci triggered fission of mitochondrial subdomains harbouring ΔOTC, but not ΔOTC clearance. Rather, Drp1 loss increased Parkin recruitment and mitophagy and decreased the selectivity of mitophagy.

These findings suggest that mitochondrial fission, rather than promoting unchecked mitophagy, restricts PINK1–Parkin activity to mitochondrial subdomains harbouring misfolded aggregates, sparing healthy mitochondria from removal.