COX7A1 enhances the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via regulating mitochondrial metabolism.
COX7A1 enhances the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via regulating mitochondrial metabolism.
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COX7A1通过调节线粒体代谢增强人NSCLC细胞对胱氨酸剥夺诱导的铁死亡的敏感性
DOI：
10.1038/s41419-022-05430-3
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发表时间：
2022-11-23
影响因子：
9
通讯作者：
Liu, Pengfei
中科院分区：
文献类型：
--
作者：
Feng, Yetong;Xu, Jiayi;Shi, Mengjiao;Liu, Rongrong;Zhao, Lei;Chen, Xin;Li, Miaomiao;Zhao, Yaping;Chen, Jiahui;Du, Wenjing;Liu, Pengfei
COX7A1 是细胞色素 c 氧化酶的一个亚基，在线粒体电子传递链 (ETC) 外围整合成多单元异聚复合物的超组装中占有重要地位。最近，一些研究表明COX7A1在癌症代谢和治疗中具有巨大潜力。然而，潜在的代谢过程和治疗机制仍不清楚。本研究通过慢病毒转导建立了 COX7A1 过表达细胞系。分别在不同的人非小细胞肺癌 (NSCLC) 细胞中进一步分析了 COX7A1 与铁死亡（一种由铁依赖性脂质过氧化驱动的新型细胞死亡形式）之间的关系。我们的结果表明，COX7A1 通过增强三羧酸（TCA）循环和线粒体 ETC 中复合物 IV 的活性，增加 NSCLC 细胞对半胱氨酸剥夺诱导的铁死亡的敏感性。同时，COX7A1 通过阻断自噬流来抑制线粒体动力学以及线粒体生物合成和线粒体自噬。自噬激活剂雷帕霉素可缓解自噬阻断，并进一步增强体外和体内NSCLC细胞对半胱氨酸剥夺诱导的铁死亡的敏感性。综上所述，我们的数据表明 COX7A1 与半胱氨酸剥夺诱导的铁死亡密切相关，并为人类 NSCLC 的治疗模式提供了新的见解。
COX7A1, a subunit of cytochrome c oxidase, holds an important position in the super-assembly which integrates into multi-unit heteromeric complexes peripherally in the mitochondrial electron transport chain (ETC). Recently, some studies indicated the significant potential of COX7A1 in cancer metabolism and therapy. However, the underlying metabolic process and therapy mechanism remain unclear. In this study, COX7A1-overexpressed cell line was established via lentivirus transduction. The relationship between COX7A1 and ferroptosis, a novel form of cell death driven by iron-dependent lipid peroxidation, was further analyzed in different human non-small-cell lung carcinoma (NSCLC) cells respectively. Our results showed that COX7A1 increased the sensitivity of NSCLC cells to the ferroptosis induced by cysteine deprivation via enhancing the tricarboxylic acid (TCA) cycle and the activity of complex IV in mitochondrial ETC. Meanwhile, COX7A1 suppressed mitochondrial dynamics as well as mitochondrial biogenesis and mitophagy through blocking autophagic flux. The autophagy activator, rapamycin, relieved the autophagic blockage and further strengthened the sensitivity to cysteine deprivation-induced ferroptosis of NSCLC cells in vitro and in vivo. Taken together, our data indicate the close association of COX7A1 with cysteine deprivation-induced ferroptosis, and provide a novel insight into the therapy mode against human NSCLC.
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影响因子：
64.5
作者：
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作者：
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