Fig. 1.

The biochemistry and pathophysiology of oncometabolites accumulation in cancer. a Fumarate and succinate accumulate in the mitochondria and in the cytosol of cells expressing loss-of-function mutants of SDH or FH. 2-Hydroxyglutarate is accumulated as a consequence of neomorphic mutations in IDH1 in the cytosol and IDH2 in the mitochondria. b Biochemical effects of the accumulated oncometabolites in the cell. The effects are color coded: red for succinate, blue for fumarate, and green for 2HG. The accumulation of succinate impairs the enzymatic activity of several aKG-dependent dioxygenases: JMJd3, which regulates chromatin structure; PHD3, which is involved in promoting neuronal apoptosis in response to NGF withdrawal; and PHD2, which primarily regulates HIFα stability. Similarly, fumarate inhibits PHD2 enzymatic activity causing HIF stabilization. 2HG accumulation impairs DNA demethylation via the inhibition of the aKG-dependent dioxygenase TET2 and affects hematopoietic cells differentiation