Mitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells

Abstract

Many tumors undergo a dramatic metabolic shift known as the Warburg effect in which glucose utilization is favored and oxidative phosphorylation is downregulated, even when oxygen availability is plentiful. However, the mechanistic basis for this switch has remained unclear. Recently several independent groups identified tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondrial molecular chaperone of the heat shock protein 90 (Hsp90) family, as a key modulator of mitochondrial respiration. Although all reports agree that this activity of TRAP1 has important implications for neoplastic progression, data from the different groups only partially overlap, suggesting that TRAP1 may have complex and possibly contextual effects on tumorigenesis. In this review we analyze these recent findings and attempt to reconcile these observations.

Keywords: ROS; TRAP1; cancer metabolism; chaperones; mitochondria.

Figure 1.

Models of the roles played by tumor necrosis factor receptor-associated protein 1 (TRAP1) in neoplasia. (A) TRAP1 stimulates respiratory complex II [succinate dehydrogenase (SDH)], the tricarboxylic acid cycle (TCA) cycle, and mitochondrial metabolism in general, maintaining the correct folding of mitochondrial proteins even under stress conditions encountered by the tumor cell. This inhibition of mitochondrial damage favors neoplastic growth. (B) TRAP1 inhibits respiration and the ensuing reactive oxygen species (ROS) generation by downregulating the activity of both SDH and respiratory complex IV. As a consequence, succinate accumulates, stabilizing the transcription factor hypoxia-inducible factor 1 alpha (HIF1a) and inducing a pseudohypoxic phenotype. At the same time, the low levels of ROS shield the tumor cell from the risk of lethal oxidative insults. Taken together, these effects of TRAP1 activity may favor the early phases of neoplastic growth. (C) In later stages of tumorigenesis, the absence of TRAP1 prompts an increase in ROS levels, leading to increased cell motility and genomic instability and thus contributing to a more aggressive phenotype. Abbreviations: OXPHOS, oxidative phosphorylation; Q, coenzyme Q; cyt c, cytochrome c; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane.