Landscape of the mitochondrial Hsp90 metabolome in tumours.

Abstract

Reprogramming of tumour cell metabolism contributes to disease progression and resistance to therapy, but how this process is regulated on the molecular level is unclear. Here we report that heat shock protein 90-directed protein folding in mitochondria controls central metabolic networks in tumour cells, including the electron transport chain, citric acid cycle, fatty acid oxidation, amino acid synthesis and cellular redox status. Specifically, mitochondrial heat shock protein 90, but not cytosolic heat shock protein 90, binds and stabilizes the electron transport chain Complex II subunit succinate dehydrogenase-B, maintaining cellular respiration under low-nutrient conditions, and contributing to hypoxia-inducible factor-1α-mediated tumorigenesis in patients carrying succinate dehydrogenase-B mutations. Thus, heat shock protein 90-directed proteostasis in mitochondria regulates tumour cell metabolism, and may provide a tractable target for cancer therapy.

• Authors: Young Chan Chae, Alessia Angelin, Sofia Lisanti, Andrew V Kossenkov, Kaye D Speicher, Huan Wang, James F Powers, Arthur S Tischler, Karel Pacak, Stephanie Fliedner, Ryan D Michalek, Edward D Karoly, Douglas C Wallace, Lucia R Languino, David W Speicher, Dario C Altieri
• Journal: Nature communications (Nat Commun) Vol. 4 Pg. 2139 ( 2013) ISSN: 2041-1723 [Electronic] England
• PMID: 23842546 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Guanidines
• HIF1A protein, human
• HSP90 Heat-Shock Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lactams, Macrocyclic
• Mitochondrial Proteins
• TRAP1 protein, human
• gamitrinib-G4
• SDHB protein, human
• Succinate Dehydrogenase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Brain Neoplasms (genetics, metabolism, pathology)
• Carcinogenesis (genetics, metabolism, pathology)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Glioblastoma (genetics, metabolism, pathology)
• Guanidines (pharmacology)
• HSP90 Heat-Shock Proteins (genetics, metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Lactams, Macrocyclic (pharmacology)
• Metabolome (drug effects, genetics)
• Mice
• Mitochondria (genetics, metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• NIH 3T3 Cells
• Succinate Dehydrogenase (genetics, metabolism)