title: 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.
authors.affiliation: Department of Pathology, Yale University School of Medicine, BML 369, 310 Cedar St, New Haven, CT 06520, USA. nuno.raimundo@yale.edu
authors.forename: Nuno
authors.initials: N
authors.lastname: Raimundo
authors.forename: Bora E
authors.initials: BE
authors.lastname: Baysal
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002952:Citric Acid Cycle / Q000235:genetics*; D005649:Fumarate Hydratase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism
chemical_list: D007521:Isocitrate Dehydrogenase; D013385:Succinate Dehydrogenase; D005649:Fumarate Hydratase