Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL.
Department of Molecular Pathology, Moffitt Cancer Center, Tampa, FL.
J Exp Med. 2020 Jun 1;217(6). doi: 10.1084/jem.20191689.
Human lung tumors exhibit robust and complex mitochondrial metabolism, likely precipitated by the highly oxygenated nature of pulmonary tissue. As ROS generation is a byproduct of this metabolism, reducing power in the form of nicotinamide adenine dinucleotide phosphate (NADPH) is required to mitigate oxidative stress in response to this heightened mitochondrial activity. Nicotinamide nucleotide transhydrogenase (NNT) is known to sustain mitochondrial antioxidant capacity through the generation of NADPH; however, its function in non-small cell lung cancer (NSCLC) has not been established. We found that NNT expression significantly enhances tumor formation and aggressiveness in mouse models of lung tumor initiation and progression. We further show that NNT loss elicits mitochondrial dysfunction independent of substantial increases in oxidative stress, but rather marked by the diminished activities of proteins dependent on resident iron-sulfur clusters. These defects were associated with both NADPH availability and ROS accumulation, suggesting that NNT serves a specific role in mitigating the oxidation of these critical protein cofactors.
人类肺部肿瘤表现出强健而复杂的线粒体代谢，这可能是由肺部组织的高度氧化性质所引发的。由于 ROS 的产生是这种代谢的副产物，因此需要以烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的形式提供还原力，以减轻对这种增强的线粒体活性的氧化应激。已知烟酰胺核苷酸转氢酶（NNT）通过生成 NADPH 来维持线粒体的抗氧化能力；然而，其在非小细胞肺癌（NSCLC）中的功能尚未确定。我们发现，在肺肿瘤起始和进展的小鼠模型中，NNT 的表达显著增强了肿瘤的形成和侵袭性。我们进一步表明，NNT 的缺失会引发线粒体功能障碍，这与氧化应激的显著增加无关，而是以依赖于固有铁硫簇的蛋白质活性降低为特征。这些缺陷与 NADPH 的可用性和 ROS 的积累有关，这表明 NNT 在减轻这些关键蛋白辅因子的氧化方面发挥了特定作用。
