Mitochondrial NAD+ in Acute Myeloid Leukemias

项目总结 靶向线粒体代谢是急性髓系白血病(AML)研究的一个活跃领域。 累积的数据表明，AML细胞的线粒体活性增强，并倾向于将谷氨酰胺作为一种 碳源与非癌细胞相比。然而，在尝试将目标定位于 这些脆弱性一次一个是治疗难治性AML细胞的持续存在，最终 导致复发或产生抵抗力。可能的原因是代谢途径的适应性 以及细胞间的可变性，要么是由于当地的环境，要么是由于遗传。 我们认为线粒体烟酰胺腺嘌呤二核苷酸(NAD)的丢失将同时 在健康细胞中以最小的毒性阻断AML使用的多种代谢途径。我们最近发表了 SLC25A51转运蛋白是人类细胞线粒体NAD水平的关键调节因子。SLC25A51是 直接负责NAD的导入，并调控SLC25A51的表达，控制其浓度 线粒体基质中的NAD。SLC25A51缺失仅导致线粒体NAD耗竭，而不是 遍及整个细胞。到目前为止，还没有办法通过选择性地耗尽线粒体NAD 一个内生的目标。值得注意的是，我们发现AML细胞对SLC25A51耗尽存在广泛的脆弱性， 包括以前被发现逃脱复合体I抑制的序列。 这一提议将确定SLC25A51在体内对AML的影响程度，阐明其作用途径 并确定控制其表达的分子机制。就像有 对于患者有限的治疗选择，这项工作的长期好处是建立一个有针对性的理论基础 通过SLC25A51检测线粒体NAD，并确定其他AML治疗方法。

PROJECT SUMMARY Targeting mitochondrial metabolism is an active area of research in Acute Myeloid Leukemia (AML). The cumulative data indicate that AML cells have heightened mitochondrial activity and prefer glutamine as a carbon source compared to noncancerous cells. Nevertheless, a challenge that emerges when trying to target these vulnerabilities one at a time is the continued presence of treatment-refractory AML cells, which ultimately result in relapse or developed resistance. The likely causes are the adaptable nature of metabolic pathways and cell-to-cell variability, either due to local environment or genetics. We propose that loss of mitochondrial nicotinamide adenine dinucleotide (NAD+) will simultaneously block multiple metabolic pathways used by AML with minimal toxicity in healthy cells. We recently published that the SLC25A51 transporter is a critical regulator of mitochondrial NAD+ levels in human cells. SLC25A51 is directly responsible for NAD+ import, and modulation of SLC25A51 expression controls the concentrations of NAD+ in the mitochondrial matrix. Loss of SLC25A51 resulted in depleted NAD+ only in mitochondria and not throughout the whole cell. Until now, there has been no way to selectively deplete mitochondrial NAD+ through an endogenous target. Notably, we have found a broad vulnerability across AML cells to SLC25A51 depletion, including lines that previously were found to escape Complex I inhibition. This proposal will determine the extent that SLC25A51 impacts AML in vivo, elucidate the pathways that this transporter supports, and determine the molecular mechanisms controlling its expression. As there are limited treatment options for patients, the long-term benefit of this work is to establish a rationale for targeting mitochondrial NAD+ through SLC25A51 and to identify additional AML therapeutic approaches.