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The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in maintaining mitochondrial metabolic homeostasis

Abhinav Joshi, Joyce Dai, Jungsoon Lee, View ORCID ProfileNastaran Mohammadi Ghahhari, View ORCID ProfileGregory Segala, Kristin Beebe, Francis T.F. Tsai, View ORCID ProfileLen Neckers, View ORCID ProfileDidier Picard
doi: https://doi.org/10.1101/679431
Abhinav Joshi
1Département de Biologie Cellulaire, Université de Genève Sciences III, 30, quai Ernest-Ansermet, CH - 1211 Genève 4, Switzerland
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Joyce Dai
2Urologic Oncology Branch, Center for Cancer Research, NCI, Bethesda, MD 20892, USA
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Jungsoon Lee
3Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Nastaran Mohammadi Ghahhari
1Département de Biologie Cellulaire, Université de Genève Sciences III, 30, quai Ernest-Ansermet, CH - 1211 Genève 4, Switzerland
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Gregory Segala
1Département de Biologie Cellulaire, Université de Genève Sciences III, 30, quai Ernest-Ansermet, CH - 1211 Genève 4, Switzerland
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Kristin Beebe
2Urologic Oncology Branch, Center for Cancer Research, NCI, Bethesda, MD 20892, USA
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Francis T.F. Tsai
3Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
4Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
5Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA
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Len Neckers
2Urologic Oncology Branch, Center for Cancer Research, NCI, Bethesda, MD 20892, USA
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  • ORCID record for Len Neckers
Didier Picard
1Département de Biologie Cellulaire, Université de Genève Sciences III, 30, quai Ernest-Ansermet, CH - 1211 Genève 4, Switzerland
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  • For correspondence: didier.picard@unige.ch
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Abstract

Background The molecular chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metabolism. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive analysis of the TRAP1 interactome and of how TRAP1 and mitochondrial metabolism mutually affect each other.

Results We show that the disruption of the gene for TRAP1 in a panel of cell lines dysregulates OXPHOS by a metabolic rewiring that induces the anaplerotic utilization of glutamine metabolism to replenish TCA cycle intermediates. Restoration of wild-type levels of OXPHOS requires full-length TRAP1. Whereas the TRAP1 ATPase activity is dispensable for this function, it modulates the interactions of TRAP1 with various mitochondrial proteins. Quantitatively by far the major interactors of TRAP1 are the mitochondrial chaperones mtHSP70 and HSP60. However, we find that the most stable stoichiometric TRAP1 complex is a TRAP1 tetramer, whose levels change in response to both a decline or an increase in OXPHOS.

Conclusions Our work provides a roadmap for further investigations of how TRAP1 and its interactors such as the ATP synthase regulate cellular energy metabolism. Our results highlight that TRAP1 function in metabolism and cancer cannot be understood without a focus on TRAP1 tetramers as potentially the most relevant functional entity.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 21, 2019.
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The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in maintaining mitochondrial metabolic homeostasis
Abhinav Joshi, Joyce Dai, Jungsoon Lee, Nastaran Mohammadi Ghahhari, Gregory Segala, Kristin Beebe, Francis T.F. Tsai, Len Neckers, Didier Picard
bioRxiv 679431; doi: https://doi.org/10.1101/679431
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The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in maintaining mitochondrial metabolic homeostasis
Abhinav Joshi, Joyce Dai, Jungsoon Lee, Nastaran Mohammadi Ghahhari, Gregory Segala, Kristin Beebe, Francis T.F. Tsai, Len Neckers, Didier Picard
bioRxiv 679431; doi: https://doi.org/10.1101/679431

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