TCA Cycle Defects and Cancer: When Metabolism Tunes Redox State

Abstract

Inborn defects of the tricarboxylic acid (TCA) cycle enzymes have been known for more than twenty years. Until recently, only recessive mutations were described which, although resulted in severe multisystem syndromes, did not predispose to cancer onset. In the last ten years, a causal role in carcinogenesis has been documented for inherited and acquired alterations in three TCA cycle enzymes, succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH), pointing towards metabolic alterations as the underlying hallmark of cancer. This paper summarizes the neoplastic alterations of the TCA cycle enzymes focusing on the generation of pseudohypoxic phenotype and the alteration of epigenetic homeostasis as the main tumor-promoting effects of the TCA cycle affecting defects. Moreover, we debate on the ability of these mutations to affect cellular redox state and to promote carcinogenesis by impacting on redox biology.

Figure 1

Redox alterations induced by TCA cycle defects. Redox alterations induced by mutations in SDH, FH, and IDH are shown. Loss of function of SDH increases ROS levels leading to DNA mutations and HIF-1α stabilization. IDH1 and IDH2 (not shown) mutations decrease GSH and NADPH levels. (R)-2-HG, produced by oncogenic mutations in IDH1 and IDH2, triggers ROS accumulation. Defects in FH stimulate nuclear translocation of Nrf2 and the transcription of antioxidant enzymes through the succination of Keap1. Enzymes and metabolites involved in tumor formation and redox alterations are in red. Blue arrows indicate TCA cycle reactions. Dotted arrows indicate pathways modulating cell redox state.