Wild-type and mutant activities of IDH1/2. Mitochondrial metabolite α-KG is produced by reduced NAD phosphate (NADP; NAPDH)-dependent isocitrate dehydrogenases IDH1 and IDH2 in the mitochondrial matrix and in the cytosol by oxidative decarboxylation of isocitrate. Mutations (IDH1/2-mut) confer these enzymes with neomorphic activity to catalyze the reduction of α-KG into oncometabolite 2-HG. High levels of 2-HG disrupt multiple cellular processes that include inhibition of α-KG–dependent dioxygenases like TET2 and histone demethylases. Professional illustration by Somersault18:24.