Revisiting the TCA cycle: signaling to tumor formation

Abstract

A role for mitochondria in tumor formation is suggested by mutations in enzymes of the TCA cycle: isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH) and fumarate hydratase (FH). Although they are all components of the TCA cycle, the resulting clinical presentations do not overlap. Activation of the hypoxia pathway can explain SDH phenotypes, but recent data suggest that FH and IDH mutations lead to tumor formation by repressing cellular differentiation. In this review, we discuss recent findings in the context of both mitochondrial and cytoplasmic components of the TCA cycle, and we propose that extrametabolic roles of TCA cycle metabolites result in reduced cellular differentiation. Furthermore, activation of the pseudohypoxia pathway likely promotes the growth of these neoplasias into tumors.

Figure 1. The TCA cycle

Shown here are the core mitochondrial components and some of the cytoplasmic enzymes that catalyze steps in the TCA cycle. The cytopasmic and mitochondrial transamination reactions involving TCA cycle metabolites were omitted for simplicity. The transport of the metabolites across the inner membrane is catalyzed by a number of carriers and antiporters, and the metabolites cross the outer membrane by diffusing through channels such as VDAC. The metabolites are shown in black, the enzymes are shown in red, and the pathways in italics. Full arrows represent the direction of a reaction, intermittent arrows represent the translocation of metabolites between mitochondria and cytoplasm. Abbreviations: IDH, isocitrate dehydrogenase.

Figure 2. Role of TCA cycle metabolites in the regulation of HIF α-subunits in hypoxic, pseudo-hypoxic and non-hypoxic conditions

The regulation of the three α-subunits (HIF-1α, HIF-2α and HIF-3α) by hydroxylation is similar, but for simplicity only HIF-1α is represented in this figure. The asparaginyl hydroxylase reaction, the phosphorylation-dependent nuclear import, and the coactivators and polymerase complex were omitted for simplicity. The HIF-1β subunit is expressed constitutively in the nucleus, and is available for dimerization with α subunits that reach the nucleus. Abbreviations: Ub, ubiquitin; HRE, hypoxia response element; TSS, transcription start site.