Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells.
Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells.
复制标题
DOI：
10.1038/s41419-023-06033-2
复制
发表时间：
2023-08-08
影响因子：
9
通讯作者：
Luo, Junjie
中科院分区：
文献类型：
--
作者：
Wang, Xuan;Ji, Yuting;Qi, Jingyi;Zhou, Shuaishuai;Wan, Sitong;Fan, Chang;Gu, Zhenglong;An, Peng;Luo, Yongting;Luo, Junjie
宫颈癌是女性癌症死亡的主要原因之一。线粒体介导的铁死亡（MMF）是最近发现的一种癌细胞死亡形式。然而，MMF 在宫颈癌中的作用和潜在机制仍不清楚。在这里，通过对线粒体跨膜候选物进行公正的筛选，我们确定线粒体载体 1 (MTCH1) 是宫颈癌中 MMF 的中心介质。 MTCH1 缺陷会破坏线粒体氧化磷酸化，同时通过降低 NAD+ 水平来升高线粒体活性氧 (ROS)。这种线粒体自主事件启动了线粒体到细胞核的逆行信号传导，涉及减少 FoxO1 核易位，随后下调关键抗铁死亡酶谷胱甘肽过氧化物酶 4 (GPX4) 的转录和活性，从而提高 ROS 并最终引发铁死亡。引人注目的是，在裸鼠异种移植模型中，靶向 MTCH1 与索拉非尼联合有效地协同抑制了宫颈癌的生长，通过主动诱导铁死亡。总之，这些发现丰富了我们对MMF机制的理解，其中MTCH1通过逆行信号传导至FoxO1-GPX4轴来控制铁死亡，并为治疗宫颈癌提供了潜在的治疗靶点。
Cervical cancer is one of the leading causes of cancer death in women. Mitochondrial-mediated ferroptosis (MMF) is a recently discovered form of cancer cell death. However, the role and the underlying mechanism of MMF in cervical cancer remain elusive. Here, using an unbiased screening for mitochondrial transmembrane candidates, we identified mitochondrial carrier 1 (MTCH1) as a central mediator of MMF in cervical cancers. MTCH1-deficiency disrupted mitochondrial oxidative phosphorylation while elevated mitochondrial reactive oxygen species (ROS) by decreasing NAD+ levels. This mitochondrial autonomous event initiated a mitochondria-to-nucleus retrograde signaling involving reduced FoxO1 nuclear translocation and subsequently downregulation of the transcription and activity of a key anti-ferroptosis enzyme glutathione peroxidase 4 (GPX4), thereby elevating ROS and ultimately triggering ferroptosis. Strikingly, targeting MTCH1 in combination with Sorafenib effectively and synergistically inhibited the growth of cervical cancer in a nude mouse xenograft model by actively inducing ferroptosis. In conclusion, these findings enriched our understanding of the mechanisms of MMF in which MTCH1 governed ferroptosis though retrograde signaling to FoxO1-GPX4 axis, and provided a potential therapeutic target for treating cervical cancer.
登录
查看更多内容
影响因子：
--
作者：
Chen G;Mo S;Yuan D
通讯作者：
Yuan D
DOI：
10.1126/science.aaw9872
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
通讯作者：
Olive KP
影响因子：
7
作者：
Du, Yunxi;Guo, Zhong
通讯作者：
Guo, Zhong
影响因子：
64.8
作者：
Luongo TS;Eller JM;Lu MJ;Niere M;Raith F;Perry C;Bornstein MR;Oliphint P;Wang L;McReynolds MR;Migaud ME;Rabinowitz JD;Johnson FB;Johnsson K;Ziegler M;Cambronne XA;Baur JA
通讯作者：
Baur JA
影响因子：
16.6
作者：
Gardell, Stephen J.;Hopf, Meghan;Pinkerton, Anthony B.
通讯作者：
Pinkerton, Anthony B.