Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Joshi, Abhinav, Dai, Li, Liu, Yanxin, Lee, Jungsoon, Ghahhari, Nastaran Mohammadi, Segala, Gregory, Beebe, Kristin, Jenkins, Lisa M., Lyons, Gaelyn C., Bernasconi, Lilia, Tsai, Francis T. F., Agard, David A., Neckers, Len, Picard, Didier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986101/
https://www.ncbi.nlm.nih.gov/pubmed/31987035
http://dx.doi.org/10.1186/s12915-020-0740-7
_version_ 1783491916332007424
author Joshi, Abhinav
Dai, Li
Liu, Yanxin
Lee, Jungsoon
Ghahhari, Nastaran Mohammadi
Segala, Gregory
Beebe, Kristin
Jenkins, Lisa M.
Lyons, Gaelyn C.
Bernasconi, Lilia
Tsai, Francis T. F.
Agard, David A.
Neckers, Len
Picard, Didier
author_facet Joshi, Abhinav
Dai, Li
Liu, Yanxin
Lee, Jungsoon
Ghahhari, Nastaran Mohammadi
Segala, Gregory
Beebe, Kristin
Jenkins, Lisa M.
Lyons, Gaelyn C.
Bernasconi, Lilia
Tsai, Francis T. F.
Agard, David A.
Neckers, Len
Picard, Didier
author_sort Joshi, Abhinav
collection PubMed
description 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 and 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.
format Online
Article
Text
id pubmed-6986101
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-69861012020-01-30 The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis Joshi, Abhinav Dai, Li Liu, Yanxin Lee, Jungsoon Ghahhari, Nastaran Mohammadi Segala, Gregory Beebe, Kristin Jenkins, Lisa M. Lyons, Gaelyn C. Bernasconi, Lilia Tsai, Francis T. F. Agard, David A. Neckers, Len Picard, Didier BMC Biol Research Article 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 and 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. BioMed Central 2020-01-27 /pmc/articles/PMC6986101/ /pubmed/31987035 http://dx.doi.org/10.1186/s12915-020-0740-7 Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Joshi, Abhinav
Dai, Li
Liu, Yanxin
Lee, Jungsoon
Ghahhari, Nastaran Mohammadi
Segala, Gregory
Beebe, Kristin
Jenkins, Lisa M.
Lyons, Gaelyn C.
Bernasconi, Lilia
Tsai, Francis T. F.
Agard, David A.
Neckers, Len
Picard, Didier
The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis
title The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis
title_full The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis
title_fullStr The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis
title_full_unstemmed The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis
title_short The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis
title_sort mitochondrial hsp90 paralog trap1 forms an oxphos-regulated tetramer and is involved in mitochondrial metabolic homeostasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986101/
https://www.ncbi.nlm.nih.gov/pubmed/31987035
http://dx.doi.org/10.1186/s12915-020-0740-7
work_keys_str_mv AT joshiabhinav themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT daili themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT liuyanxin themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT leejungsoon themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT ghahharinastaranmohammadi themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT segalagregory themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT beebekristin themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT jenkinslisam themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT lyonsgaelync themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT bernasconililia themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT tsaifrancistf themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT agarddavida themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT neckerslen themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT picarddidier themitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT joshiabhinav mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT daili mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT liuyanxin mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT leejungsoon mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT ghahharinastaranmohammadi mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT segalagregory mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT beebekristin mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT jenkinslisam mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT lyonsgaelync mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT bernasconililia mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT tsaifrancistf mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT agarddavida mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT neckerslen mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis
AT picarddidier mitochondrialhsp90paralogtrap1formsanoxphosregulatedtetramerandisinvolvedinmitochondrialmetabolichomeostasis