Abstract：
Cell models of mitochondrial complex Ⅰ (CⅠ) deficiency display significant elevations in reactive oxygen species (ROS) levels and an increase in cellular apoptosis. However, the underlying mechanisms governing anti-apoptotic processes in CⅠ-deficient cells remain elusive. Here, we introduced a mutation in NDUFS7, a crucial subunit of CI, in HEK293T cells and found that the absence of NDUFS7 resulted in reduced cell proliferation, elevated cell death, and increased susceptibility to oxidative stress. Mechanismly, we revealed that the upregulation of SLC7A11 played a crucial role in mitigating cell death resulting from NDUFS7 deficiency. Specifically, the increased expression of SLC7A11 enhanced cystine import, which subsequently reduced cell death by promoting the biosynthesis of reduced glutathione (GSH). Collectively, our findings suggest that SLC7A11-mediated cystine import, representing a novel pathway independent of NADPH production, plays a vital role in protection against NDUFS7 deficiency-induced cell death. This novel pathway provides potential insights into the understanding of pathogenic mechanisms and the therapeutic management of mitochondrial disorders associated with CⅠ deficiency.
摘要：
线粒体复合物Ⅰ（CⅠ）缺乏的细胞模型显示活性氧（ROS）水平显着升高，细胞凋亡增加。然而,控制CⅠ缺陷细胞抗凋亡过程的潜在机制仍然难以捉摸。这里,我们在HEK293T细胞中引入了NDUFS7（CI的关键亚基）的突变，并发现NDUFS7的缺失导致细胞增殖减少，细胞死亡升高，和增加对氧化应激的敏感性。机械地，我们揭示了SLC7A11的上调在减轻因NDUFS7缺陷导致的细胞死亡中起着至关重要的作用.具体来说,SLC7A11表达的增加增强了胱氨酸的输入，随后通过促进还原型谷胱甘肽（GSH）的生物合成来减少细胞死亡。总的来说，我们的研究结果表明，SLC7A11介导的胱氨酸导入，代表一种独立于NADPH产生的新通路，在针对NDUFS7缺陷诱导的细胞死亡的保护中起着至关重要的作用。这种新的途径为了解与CⅠ缺乏相关的线粒体疾病的致病机制和治疗管理提供了潜在的见解。
