The mitochondrial chaperone TRAP-1 regulates the glutamine metabolism in tumor cells

TRAP-1 OE cells exhibit metabolic rewiring. TRAP-1 OE cells enhance glutamine metabolism through HIF2α, SLC1A5, and GLS axis to fuel the TCA cycle upon glucose deprivation. Although a direct interaction of TRAP-1 with them is not observed in this study, we observed a correlation of this axis facilitating metabolic rewiring. This study also provides information that enhanced glutamine metabolism favors oxidative phosphorylation. [Display omitted] •TRAP-1 is involved in maintaining mitochondrial integrity.•TRAP-1 favors aerobic glycolysis and decreases mitochondrial dependency in presence of glucose.•TRAP-1 favors oxidative phosphorylation upon glucose deprivation or pharmacological inhibition of glycolysis.•TRAP-1 enhances glutamine utilization in the absence of glucose through the HIF2α-SLC1A5-GLS axis. Understanding cancer cell metabolism always provides information on hidden dimensions of tumor adaptations. Warburg's theory that cancer cells opt for aerobic glycolysis over the mitochondrial oxidative phosphorylation (OXPHOS) system is widely accepted. However, the hypothesis does not explain the mitochondrion's role in these cells. Here, we demonstrate that intact mitochondria are used for anaplerotic functions and ATP production by utilizing glutamine with the help of mitochondrial chaperone TRAP-1 (Tumor Necrosis Factor Receptor-associated Protein 1). TRAP-1 otherwise promotes aerobic glycolysis by lowering the mitochondrial OXPHOS in the presence of glucose. Here, we show that TRAP-1 maintains mitochondrial integrity and augments glutamine metabolism upon glucose deprivation to meet the cellular energy demand. The enhanced PER and ECAR correlating with increased ATP production suggest that glutamine fuels mitochondria in the presence of TRAP-1. We also found that TRAP1-dependent glutamine utilization involves the HIF2α-SLC1A5-GLS axis and is independent of hypoxia. Subsequently, we show that the metastatic potential of tumor cells is linked with glucose utilization, whereas the proliferative potential is linked with both glucose and glutamine utilization. Our findings establish that TRAP-1 contributes to enhanced glutamine utilization through the HIF2α-SLC1A5-GLS axis. Our results endow that TRAP-1 inhibitors can be potential drug candidates to combat tumor metabolism. Therefore, their use, either alone or in combination with existing chemotherapeutic agents, may target tumor metabolism and improve anticancer treatment response.