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. 1. Introduction Cancer cells differ from normal ones due to a plethora of oncogenes-driven biochemical changes designed to sustain an high rate of growth and proliferation [1]. The first tumor-specific alteration in metabolism was reported at the beginning of the 20th century by Warburg [2]. His observations demonstrated that cancer cell metabolism relies on an increased glycolytic flux maintained even in the presence of oxygen (“aerobic glycolysis” or “Warburg effect”), without an associated increase in oxidative phosphorylation rate. The switch from respiration to glycolysis has usually been considered a consequence, rather than a cause, of cancer. However, in the last decade, the discovery that inherited and acquired alterations in some enzymes of tricarboxylic acid (TCA) cycle have a causal role in carcinogenesis has changed this viewpoint, pointing towards altered metabolism as the underlying hallmark of neoplastic transformation. These alterations consist of germline defects in genes encoding subunits of SDH and FH, as well as somatic mutations in coding sequence for IDH. Together with metabolomics studies documenting the alteration of HIF-dependent signaling pathway and epigenetic dynamics as main tumor-promoting effects of these mutations, a mounting body of evidence also supports how alterations in the TCA cycle enzymes may favor tumorigenesis by impacting on cellular redox state. Therefore, in this paper, we summarize the prooncogenic defects in the TCA cycle enzymes discussing their involvement in the tuning of redox environment and the engagement of redox-dependent tumorigenic signaling. 2. Fundamentals
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