2. Academic Validation
  3. 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

  • Cell Death Dis. 2023 Aug 8;14(8):508. doi: 10.1038/s41419-023-06033-2.
Xuan Wang # 1,  Yuting Ji # 1 2 3,  Jingyi Qi 1,  Shuaishuai Zhou 1,  Sitong Wan 1,  Chang Fan 1,  Zhenglong Gu 2 3,  Peng An 4,  Yongting Luo 5,  Junjie Luo 6
Affiliations

Affiliations

  • 1 Department of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, 100193, Beijing, China.
  • 2 Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, 511400, Guangzhou, China.
  • 3 Institute of Life Sciences, Fudan University, 200433, Shanghai, China.
  • 4 Department of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, 100193, Beijing, China. an-peng@cau.edu.cn.
  • 5 Department of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, 100193, Beijing, China. luo.yongting@cau.edu.cn.
  • 6 Department of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, 100193, Beijing, China. luojj@cau.edu.cn.
  • # Contributed equally.
PMID: 37550282 DOI: 10.1038/s41419-023-06033-2
Abstract

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.

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