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

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 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.

Identification of an energy metabolism‑related gene signature in ovarian cancer prognosis

“…Previous studies have demonstrated that abnormal metabolism is one of the markers of cancer cells, and that there are differences between healthy and tumor cells in energy metabolism (58)(59)(60); in addition, various catabolic pathways, for example, glycolysis, OXPHOS and fatty acid metabolism, are involved in energy metabolism (61). In the current study, RNA-seq data were used to detect local energy metabolism-related gene expression status and their prognostic value for patients with ovarian cancer.…”

Small-Molecule Activity-Based Probe for Monitoring Ubiquitin C-Terminal Hydrolase L1 (UCHL1) Activity in Live Cells and Zebrafish Embryos

“…In order to gain insight into the protein abundances for each of the identified targets, we searched the PRIDE repository for a recent data set of a total cellular proteome quantitation MS analysis in HEK293T cells and used the one published by Joshi et al (PRIDE project PXD015828). 39 The iBAQ values corresponding to our identified targets are shown in Supporting Information Figure S4 . The pull-down efficiency between UCHL1 and PARK7 is hardly affected by their relative protein abundances because these are very similar.…”

“…*ES1 has been annotated as glutamine amidotransferase-like class 1 domain-containing protein 3A or 3B (GATD3A or GATD3B). Reference intensities (iBAQ values) of corresponding proteins in wild-type HEK293T cells 39 are shown in Supporting Information Figure S4 .…”

Molecular Chaperones: Molecular Assembly Line Brings Metabolism and Immunity in Shape

“…TRAP1, a mitochondrial heat shock protein in the HSP90 family, controls a myriad of physiological roles, including cell proliferation, differentiation and survival [ 84 , 85 , 86 ]. It has been shown that TRAP1 can mediate the metabolic switch from oxidative phosphorylation (OXPHOS) to glycolysis in cancer cells [ 84 , 87 ]. Briefly, TRAP1 inhibits OXPHOS by interacting with complex II (known as succinate dehydrogenase, SDH) and/or complex IV of the mitochondrial respiratory chain, leading to an accumulation of intracellular succinate ( Figure 1 ).…”