Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy

Autophagy, the primary recycling pathway of cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the response to cellular stress. The Hsp90-Cdc37 chaperone complex coordinately regulates the activity of select kinases to orchestrate many facets of the stress response. Although both maintain mitochondrial integrity, the relationship between Hsp90-Cdc37 and Autophagy has not been well characterized. ULK1, one of the mammalian homologs of yeast Atg1, is a serine-threonine kinase required for Mitophagy. Here we show that the interaction between ULK1 and Hsp90-Cdc37 stabilizes and activates ULK1, which in turn is required for the phosphorylation and release of Atg13 from ULK1, and for the recruitment of Atg13 to damaged mitochondria. Hsp90-Cdc37, ULK1, and Atg13 phosphorylation are all required for efficient mitochondrial clearance. These findings establish a direct pathway that integrates Ulk1- and Atg13-directed Mitophagy with the stress response coordinated by HSP90 and Cdc37.