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Mitochondria are the energy-producing “machines” within cells that act as the gatekeepers of cell death. Aged or damaged mitochondria produce excessive amounts of free radicals that can damage cells and contribute to the development of diseases such as cancer and diabetes in children and adults. Therefore, cells must recognize and remove dysfunctional mitochondria to remain healthy. Defective mitochondria can be eliminated by a specialized form of autophagy called mitophagy. This process must be properly regulated so that dysfunctional mitochondria do not accumulate to cause disease, and functional mitochondria are not unnecessarily depleted, leaving the cell without sufficient energy.
Recent work from the laboratory of Mondira Kundu, MD, PhD (Pathology), published in Molecular Cell1, focuses on how cells use autophagy to remove damaged mitochondria. Autophagy, the primary recycling pathway of cells, plays a crucial role in mitochondrial quality control under normal growth conditions and in response to cellular stress. Many types of tumors exploit the autophagy pathway to survive and thrive in response to the stresses in the tumor microenvironment (e.g., nutrient deprivation, low oxygen concentration, excessive heat) that are toxic to most cells.
The Hsp90-Cdc37 chaperone complex is required for proper functioning of numerous signaling molecules, and in this way, the complex orchestrates many facets of cellular response to stress, including the maintenance of mitochondrial integrity. Certain cancers (e.g., multiple myeloma, liver cancer, and pancreatic cancer) depend on Hsp90 and Cdc37 for survival, and drugs targeting this pathway are currently being incorporated into anticancer clinical trials.
Although it is well established that autophagy and the Hsp90-Cdc37 chaperone complex are both involved in mitochondrial quality control, the relationship between Hsp90-Cdc37 and autophagy was not well characterized. Dr. Kundu and colleagues demonstrated that Hsp90-Cdc37 stabilizes and activates Ulk1, which is a key regulator of autophagy and a homologue of yeast Atg1. By using a variety of genetic and biochemical approaches, the researchers found that the activity of the Hsp90-Cdc37 complex is an essential determinant of the concentration and function of Ulk1 in a cell. “This research may provide a mechanism for the increased expression of Ulk1 protein in certain types of cancer,” said Dr. Kundu.
Ulk1 is a kinase that phosphorylates substrates and regulates their function. However, the way in which these phosphorylation events regulate autophagy was not known. Dr. Kundu’s team demonstrated that after the Hsp90-Cdc37 complex activates Ulk1, the latter phosphorylates its substrate Atg13. Atg13 phosphorylation promotes its release from the complex and recruitment to damaged mitochondria, where Atg13 facilitates autophagy-mediated clearance. The findings from this study link Hsp90-Cdc37, Ulk1, and Atg13 in a direct pathway that is essential for efficient mitochondrial clearance and identify the Hsp90-Cdc37 complex as the on–off switch for Ulk1 function. Targeting the interaction between Ulk1 and the Hsp90-Cdc37 complex may represent a new approach for inhibiting autophagy and impairing a cell’s ability to cope with mitochondrial stress, both of which are crucial for the survival of tumor cells.
1Joo JH, Dorsey FC, Joshi A, Hennessy-Walters KM, Rose KL, McCastlain K, Zhang J, Iyengar R, Jung CH, Suen DF, Steeves MA, Yang CY, Prater SM, Kim DH, Thompson CB, Youle RJ, Ney PA, Cleveland JL, Kundu M. Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy. Mol Cell Aug 19;43(4):572-85, 2011. doi: 10.1016/j.molcel.2011.06.018. PubMed PMID: 21855797; PubMed Central PMCID: PMC3485687. Abstract | Full Text