Hsp90-Cdc37 Chaperone Complex Regulates Ulk1- and Atg13-Mediated Mitophagy

Joung Hyuck Joo, Frank C. Dorsey, Aashish Joshi, Kristin M. Hennessy-Walters, Kristie L. Rose, Kelly McCastlain, Ji Zhang, Rekha Iyengar, Chang Hwa Jung, Der Fen Suen, Meredith A. Steeves, Chia Ying Yang, Stephanie M. Prater, Do Hyung Kim, Craig B. Thompson, Richard J. Youle, Paul A. Ney, John L. Cleveland, Mondira Kundu

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170 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)572-585
Number of pages14
JournalMolecular Cell
Issue number4
StatePublished - Aug 19 2011

Bibliographical note

Funding Information:
We are grateful to Charles J. Sherr (St. Jude Children's Research Hospital [SJCRH], Memphis, TN) for providing Cdc37 antibody; Emily Tresse (SJCRH) for the LPC-mCherry-EGFP-LC3b construct; Toshifumi Tomoda (Beckman Research Institute of City of Hope, Duarte, CA) for Flag-Ulk1 deletion constructs; Sharon Tooze (London Research Institute, Cancer Research UK, London, UK) for providing an Atg13 antibody; Mark Hall (The Scripps Research Institute [TSRI], Jupiter, Florida) for providing the MSCV-Gateway-IRES-GFP vector; Reuben Shaw (The Salk Institute for Biological Studies, La Jolla, CA) for providing ulk1 −/− MEFs stably expressing ulk2 shRNA; Jennifer Moore (SJCRH) for assistance with generation of MEFs; Aaron Poole (SJCRH), Valerie Cavett (TSRI), Chunying Yang (TSRI), and Laura Alsina (TSRI) for technical support; the Proteomics Core facilities of Scripps Florida (TSRI) and the University of Pennsylvania; the Biomedical Imaging Core facilities at SJCRH (Samuel Connell, Jennifer Peters, and Sharon Frase) and University of Pennsylvania (Neelima Shaw and Ray Meade); and Robert Matts (Oklahoma State University) for helpful discussions. This research was partially supported by grants from the National Institutes of Health to M.K. (HL084199), F.C.D. (CA123777), J.L.C. (CA076379), P.A.N. (DK074519), D.-H.K. (GM097057), and C.B.T. (CA099179); the NINDS intramural program to R.Y; the Burroughs Welcome Fund to M.K.; the American Society of Hematology to M.K.; and the American Diabetes Association to D.-H.K. (ADA 7-07-CD-08); by monies from the State of Florida to J.L.C. at Scripps Florida; and by monies from the American Lebanese Syrian Associated Charities (ALSAC) to P.A.N. and M.K.


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