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SLC25A51 selectively imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining cell respiration. We observed elevated expression of SLC25A51 that correlated with poorer outcomes in patients with acute myeloid leukemia (AML), and we sought to determine the role SLC25A51 may serve in this disease. We found that lowering SLC25A51 levels led to increased apoptosis and prolonged survival in orthotopic xenograft models. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from mitochondrial oxidative pathways, notably without increased glycolytic flux. Depletion of SLC25A51 combined with 5-azacytidine treatment limits expansion of AML cells in vivo. Together, the data indicate that AML cells upregulate SLC25A51 to decouple mitochondrial NAD+/NADH for a proliferative advantage by supporting oxidative reactions from a variety of fuels. Thus, SLC25A51 represents a critical regulator that can be exploited by cancer cells and may be a vulnerability for refractory AML.
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•Elevated SLC25A51 expression correlates with poorer outcomes in patients with AML•AML cells rely on a SLC25A51-dependent oxidative NAD+/NADH ratio for tumorigenesis•Its loss targets the oxidative mitochondrial compartment in vulnerable cell types•SLC25A51 depletion combines with 5-azacytidine to limit AML cell expansion
NAD+ is essential for oxidative metabolism. Lu et al. show that acute myeloid leukemic cells upregulate mitochondrial NAD+ transporter, SLC25A51, to support an oxidative NAD+/NADH ratio specifically in this compartment for a proliferative advantage. Depletion of SLC25A51 reduced tumor burden in orthotopic xenograft models.