IDH2 and acute myeloid leukemia: Here we show that rare variants affecting both mitochondrially encoded and nuclear-encoded complex I genes display near-mutual exclusivity with somatically acquired mutations in IDH1, but not IDH2. AML cells with rare complex I variants, or mutations in IDH1 or IDH2, display attenuated mitochondrial respiration, however heightened sensitivity to IACS-010759 is only observed for IDH1-mutant AML.