Abstract
BackgroundThe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
The molecular chaperone TRAP1, the mitochondrial isoform of cytosolic heat shock protein 90 (HSP90), remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metabolism
TRAP1 has been proposed to play a key role in the induction of the Warburg phenotype of cancer cells, conflicting studies [18, 19] clearly call for additional research to understand how TRAP1 regulates the mitochondrial metabolism
Loss of TRAP1 increases oxidative phosphorylation (OXPHOS) due to an anaplerotic increase in glutamine uptake and metabolism The gene TRAP1 was disrupted in HEK293T, HCT116, A549, and UMUC3 cells using the CRISPR/Cas9 technology and the workflow presented in Additional file 1: Figure S1a
Summary
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. 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. TRAP1 expression was found in several studies to be inversely correlated with oxidative phosphorylation (OXPHOS) and OXPHOS-coupled ATP synthesis in different cell types [3, 4] These data suggested that TRAP1 is a negative regulator of mitochondrial OXPHOS, but the underlying molecular mechanisms have remained controversial. TRAP1 has been proposed to play a key role in the induction of the Warburg phenotype of cancer cells, conflicting studies [18, 19] clearly call for additional research to understand how TRAP1 regulates the mitochondrial metabolism. Only a more detailed examination of how TRAP1 and cellular metabolism affect each other will provide sufficient biological insights to evaluate TRAP1 as a potential drug target for the treatment of cancer and other diseases with a metabolic imbalance
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