ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy

Abstract

Autophagy eliminates dysfunctional mitochondria in an intricate process known as mitophagy. ULK1 is critical for the induction of autophagy, but its substrate(s) and mechanism of action in mitophagy remain unclear. Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3. A ULK1-binding-deficient mutant of FUNDC1 prevents ULK1 translocation to mitochondria and inhibits mitophagy. Finally, kinase-active ULK1 and a phospho-mimicking mutant of FUNDC1 rescue mitophagy in ULK1-null cells. Thus, we conclude that FUNDC1 regulates ULK1 recruitment to damaged mitochondria, where FUNDC1 phosphorylation by ULK1 is crucial for mitophagy. Synopsis This study shows that ULK1 translocates to damaged mitochondria and phosphorylates FUNDC1, which is crucial for organelle elimination through mitophagy. ULK1-induced phosphorylation enhances FUNDC1 interaction with LC3. Hypoxia and mitochondrial uncouplers upregulate ULK1 and induce its translocation to damaged mitochondria ULK1 recruitment to mitochondria is regulated by its binding to FUNDC1 At mitochondria, ULK1 directly phosphorylates FUNDC1 at serine-17, which is necessary for FUNDC1-LC3 binding and colocalization Serine-17 phosphorylation is required for mitophagy in response to hypoxia and FCCP This study shows that ULK1 translocates to damaged mitochondria and phosphorylates FUNDC1, which is crucial for organelle elimination through mitophagy. ULK1-induced phosphorylation enhances FUNDC1 interaction with LC3. © 2014 The Authors.