The Mitochondrial Chaperone TRAP1 Promotes Neoplastic Growth by Inhibiting Succinate Dehydrogenase

Abstract

SummaryWe report that the mitochondrial chaperone TRAP1, which is induced in most tumor types, is required for neoplastic growth and confers transforming potential to noncancerous cells. TRAP1 binds to and inhibits succinate dehydrogenase (SDH), the complex II of the respiratory chain. The respiratory downregulation elicited by TRAP1 interaction with SDH promotes tumorigenesis by priming the succinate-dependent stabilization of the proneoplastic transcription factor HIF1α independently of hypoxic conditions. These findings provide a mechanistic clue to explain the switch to aerobic glycolysis of tumors and identify TRAP1 as a promising antineoplastic target.

TRAP1 Provides Protection Against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction

“…A similar preservation of complex IV activity was reported in rat brains overexpressing TRAP1 after cerebral ischemia [12]. It has also been reported that TRAP1 binds to and inhibits succinate dehydrogenase (complex II) [25]. Indeed, we found that TRAP1 overexpression adversely affects complex II activity in HL-1 cardiomyocytes.…”

Deletion of the Mitochondrial Chaperone TRAP-1 Uncovers Global Reprogramming of Metabolic Networks

“…In these experiments, citrate synthase-normalized (Figure S2C) mitochondrial Complex I activity was not significantly different between WT and TRAP-1 −/− mice (Figure 2A), as assessed in three independent mitochondrial preparations (Figure 2B). Complex II activity, which was proposed to be inhibited by TRAP-1 (Sciacovelli et al, 2013), was instead unchanged between the two animal groups (Figure 2C–D). In addition, treatment with Gamitrinib, a small molecule antagonist that target TRAP-1/Hsp90 selectively in mitochondria (Chae et al, 2012), inhibited Complex II activity in WT mitochondria, but had no effect on TRAP-1 −/− samples (Figure 2E), consistent with the absence of its target, TRAP-1, in these cells.…”

“…Together with the identification of mutations in oxidative phosphorylation subunits that produce “oncometabolites” (Lu et al, 2012; Turcan et al, 2012), or stabilize oncogenes, such as HIF1α (Selak et al, 2005), this has suggested that mitochondrial bioenergetics has limited (if any) role in cancer (Ward and Thompson, 2012), and may actually function as a “tumor suppressor” (Frezza et al, 2011). In this context, the role of mitochondrial Hsp90s in bioenergetics has become controversial, as conflicting reports in the literature have claimed that TRAP-1 actually inhibits SDHB activity in tumor cells, promoting the accumulation of the oncometabolite, succinate (Sciacovelli et al, 2013), or, conversely, acts as a potential “tumor suppressor” through stimulation of glucose metabolism (Yoshida et al, 2013). …”

SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I

“…The importance of Complex I-dependent oxidants is further highlighted by our recent observation that the Gold(III)-dithiocarbamato compound AUL12 induces neoplastic cell death by enhancing ROS generation at Complex I, thus triggering multiple signalling pathways that eventually lead to PTP opening [37]. The importance of regulation of respiratory chain complexes in cancer cells is becoming increasingly clear, as exemplified by the recent observations that activity of Complex I is inhibited in models of K-Ras-driven tumorigenesis [47], and that down-regulation of Complex II by the mitochondrial chaperone TRAP1 creates a pseudohypoxic phenotype that promotes tumorigenesis [48]. …”