SLC25A51 Decouples the Mitochondrial NAD/NADH Ratio to Control Proliferation of AML Cells

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2024 Feb 14

PMID 38354740

Authors

Mu-Jie Lu

Jonathan Busquets

Valeria Impedovo

Crystal N Wilson

Hsin-Ru Chan

Yu-Tai Chang

William Matsui

Stefano Tiziani

Xiaolu A Cambronne

Affiliations

Soon will be listed here.

Abstract

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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