Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

Abstract

TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidation, and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial molecular chaperone may act as a tumor suppressor.M olecular chaperones help to maintain cellular homeostasis.The heat-shock protein 90 (HSP90) family of molecular chaperones is highly conserved from bacteria to mammals. HSP90 itself is an essential molecular chaperone found in the cytoplasm and nucleus of all eukaryotic cells (1, 2). In multicellular eukaryotes, the HSP90 family includes the mitochondrial chaperone TRAP1 (TNF receptor-associated protein), which shares 50% sequence similarity with HSP90. Although TRAP1 binds and hydrolyzes ATP in an analogous manner to HSP90 (3), its cellular function is less well understood. Thus, although many HSP90-dependent proteins ("clients") and interacting cochaperones have been described (www.picard.ch/downloads/Hsp90interactors.pdf), the validated list of TRAP1-dependent clients is quite small and TRAP1-interacting cochaperones, if they exist, have yet to be identified (4).Several studies have suggested that TRAP1 plays a cytoprotective role by buffering reactive oxygen species (ROS)-mediated oxidative stress (5, 6), and others have reported that TRAP1 overexpression attenuates ROS production (7). The antioxidant properties of TRAP1, together with its reported ability to regulate opening of the mitochondrial permeability transition pore (8, 9), may contribute to its antiapoptotic activity (4). For these reasons, TRAP1 has been proposed as an anticancer molecular target, and first-generation inhibitors have shown some anticancer activity in preclinical models (10). However, these inhibitors do not distinguish between HSP90 and TRAP1 (11), and TRAP1 expression in cancer is variable but HSP90 comprises as much as 5% of...

Mitochondrial ROS in the prohypertensive immune response

“…At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display enhanced invasiveness (13). This could indicate a tight correlation between metabolic phenotype of immune cells and ROS.…”

ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

“…However, whether its roles are uniformly oncogenic or not is now a matter of intense debate. Interestingly, Yoshida and colleagues [3] propose a more subtle reading of TRAP1 roles in the regulation of cellular metabolism and its impact on tumorigenesis. In fact, an inverse correlation between TRAP1 expression and tumor stage in cervical, bladder, and clear cell renal cell carcinoma was demonstrated.…”

“…It has already been demonstrated that TRAP1 stays at the crossroad of these three processes. In fact, i) TRAP1 contributes to the tumor's switch to aerobic glycolysis through inhibition of succinate dehydrogenase, the complex II of the mitochondrial respiratory chain [3,50]; ii) TRAP1 is part of a pro-survival signalling pathway aimed at evading the toxic effects of oxidants and anticancer drugs, and this effect is mediated by its capacity to protect mitochondria against damaging stimuli via a decrease of ROS generation (reviewed 51); iii) TRAP1 controls protein homeostasis through a direct involvement in the regulation of protein synthesis and co-translational protein degradation [13]. Recently, striking evidence suggests that transcription and translation can also be coupled in eukaryotes through the "remote controlling" of translation by the transcription apparatus, namely by Rpb4p and Rpb7p proteins, two components of RNA polymerase II [52].…”

Guardian of the Furnace: Mitochondria, TRAP1, ROS and stem cell maintenance

“…Interestingly, Hua et al (35) showed that the silencing of TRAP1 through siRNA increased ROS accumulation, whereas TRAP1 overexpression decreased ROS production in cancer cell models. Recently, Yoshida et al (36) have shown that TRAP1 downregulation results in altered mitochondrial activity, specifically resulting in increased complex IV activity in, among others, human cervical HeLa cells and mouse adult fibroblasts derived from TRAP12/2 knockout mice. Seemingly, this indicates conserved mammalian function and tight regulation of the shift between oxidative phosphorylation and aerobic glycolysis.…”