SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux

Abstract

AbstractSLC25A51 imports oxidized NAD+into the mitochondrial matrix and is required for sustaining oxidative metabolism in human mitochondria. We observed that higher expression of SLC25A51 correlated with poorer survival in Acute Myeloid Leukemia (AML) patient data. Given AML’s dependency on oxidative cell metabolism, we sought to determine the role SLC25A51 may serve in this disease. We found that depleting SLC25A51 in AML cells led to increased apoptosis, as well as prolonged survival in a xenograft model. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from oxidative pathways and promoted glutamine utilization for reductive carboxylation to support aspartate production. Consequently, SLC25A51 loss sensitized AML cells to glutamine deprivation and glutaminase inhibitor CB-839. Together, the work highlights connections between SLC25A51 and oxidative mitochondrial flux in AML. We identified a rationale for targeting SLC25A51 in myeloid cancers with potential for a therapeutic window, especially when coupled with glutaminase inhibition.Statement of significanceThis investigation describes an approach to directly modulate the tricarboxylic acid cycle as a potential vulnerability in oxidative tumors. Using AML models, the work is an inaugural look into SLC25A51’s role supporting oxidative mitochondrial metabolism and identifies SLC25A51 levels as a potential marker for stratification of AML.