SLC25A51 可使线粒体 NAD+/NADH 比率脱钩,从而控制 AML 细胞的增殖。

Cell metabolism Pub Date : 2024-04-02 Epub Date: 2024-02-14 DOI:10.1016/j.cmet.2024.01.013
Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Crystal N Wilson, Hsin-Ru Chan, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu A Cambronne
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引用次数: 0

摘要

SLC25A51 选择性地将氧化的 NAD+ 导入线粒体基质,是维持细胞呼吸所必需的。我们观察到 SLC25A51 表达的升高与急性髓性白血病(AML)患者较差的预后有关,因此我们试图确定 SLC25A51 在这种疾病中可能发挥的作用。我们发现,降低 SLC25A51 水平会导致凋亡增加,并延长正位异种移植模型的存活时间。代谢通量分析表明,耗竭SLC25A51会将通量从线粒体氧化途径分流出去,特别是不会增加糖酵解通量。SLC25A51的耗竭与5-氮杂胞苷处理相结合,限制了AML细胞在体内的扩增。这些数据共同表明,AML 细胞会上调 SLC25A51,使线粒体 NAD+/NADH 解耦,从而通过支持多种燃料的氧化反应获得增殖优势。因此,SLC25A51代表了一种可被癌细胞利用的关键调节因子,可能是难治性急性髓细胞性白血病的易感因素。
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SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.

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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