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Trends Mol Med. 2011 Nov;17(11):641-9. doi: 10.1016/j.molmed.2011.06.001. Epub 2011 Jul 20.

Revisiting the TCA cycle: signaling to tumor formation.

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Department of Pathology, Yale University School of Medicine, BML 369, 310 Cedar St, New Haven, CT 06520, USA.


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.

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