It was recently suggested that TRAP1 clients include subunits of F-ATP synthase, even if a characterization of such interactions and of their functional effects was lacking. In this scenario, the identification of further TRAP1 interactors is mandatory to better dissect its functions. In turn, HIF1 activation increases TRAP1 expression, and TRAP1 is crucial in maintaining a low oxygen consumption rate under hypoxia, a feature whose importance extends beyond conditions of tumor growth. This favors neoplastic growth, and genetic or pharmacological TRAP1 inhibition hampers tumorigenicity in several models of neoplastic progression, whereas TRAP1 induction correlates with drug resistance, progression and metastatic spreading in a number of malignancies. For instance, SDH inhibition by TRAP1 establishes a pseudohypoxic phenotype mediated by succinate-dependent induction of the HIF1 transcriptional program. TRAP1 regulates the metabolic adaptations of tumor cells to the changing conditions experienced in the microenvironment. TRAP1-induced formation of different protein assemblies, together with a fine pitching of its interactions by post-translational modifications (PTMs), could flexibly tune client functions, matching the activity of diverse biochemical circuits with the metabolic needs of the cell. A recent survey identified other putative TRAP1 interactors, called clients, suggesting that its effects on cell bioenergetics are shaped by the engagement of different client subsets. The mitochondrial paralog of the HSP90 chaperone family TRAP1 is an important bioenergetic regulator that down-modulates oxidative phosphorylation (OXPHOS) by inhibiting cytochrome c oxidase and succinate dehydrogenase (SDH). Our data identify TRAP1 as an F-ATP synthase regulator that can influence cell bioenergetics and survival and can be targeted in pathological conditions where these processes are dysregulated, such as cancer. Conversely, CyPD outcompetes the TRAP1 inhibitory effect on the channel. Electrophysiological measurements indicate that TRAP1 directly inhibits a channel activity of purified F-ATP synthase endowed with the features of the permeability transition pore (PTP) and that it reverses PTP induction by CyPD, antagonizing PTP-dependent mitochondrial depolarization and cell death. TRAP1 competes with the peptidyl-prolyl cis- trans isomerase cyclophilin D (CyPD) for binding to the oligomycin sensitivity-conferring protein (OSCP) subunit of F-ATP synthase, increasing its catalytic activity and counteracting the inhibitory effect of CyPD. Here we show that TRAP1 interacts with F-ATP synthase, the protein complex that provides most cellular ATP. Binding of the mitochondrial chaperone TRAP1 to client proteins shapes bioenergetic and proteostatic adaptations of cells, but the panel of TRAP1 clients is only partially defined.
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