Landscape of the mitochondrial Hsp90 metabolome in tumours

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 and Dario C. Altieri ()
Additional contact information
Young Chan Chae: Prostate Cancer Discovery and Development Program, The Wistar Institute
Alessia Angelin: Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia
Sofia Lisanti: Prostate Cancer Discovery and Development Program, The Wistar Institute
Andrew V. Kossenkov: Molecular and Cellular Oncogenesis Program and Center for Systems and Computational Biology, The Wistar Institute
Kaye D. Speicher: Molecular and Cellular Oncogenesis Program and Center for Systems and Computational Biology, The Wistar Institute
Huan Wang: Molecular and Cellular Oncogenesis Program and Center for Systems and Computational Biology, The Wistar Institute
James F. Powers: Tufts Medical Center
Arthur S. Tischler: Tufts Medical Center
Karel Pacak: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Stephanie Fliedner: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Ryan D. Michalek: Metabolon, Inc
Edward D. Karoly: Metabolon, Inc
Douglas C. Wallace: Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia
Lucia R. Languino: Prostate Cancer Discovery and Development Program, The Wistar Institute
David W. Speicher: Molecular and Cellular Oncogenesis Program and Center for Systems and Computational Biology, The Wistar Institute
Dario C. Altieri: Prostate Cancer Discovery and Development Program, The Wistar Institute

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3139

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