Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells

• Published in: Cell death & disease 2023-08, Vol.14 (8), p.508-508, Article 508
• Main Authors: Wang, Xuan, Ji, Yuting, Qi, Jingyi, Zhou, Shuaishuai, Wan, Sitong, Fan, Chang, Gu, Zhenglong, An, Peng, Luo, Yongting, Luo, Junjie
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 13/44; 13/89; 13/95; 14/19; 14/28; 38/77; 45/41; 45/90; 631/67; 631/80; 64/60; 82/51; 82/80; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Cell Death - physiology; Cervical cancer; Female; Ferroptosis; FOXO1 protein; Glutathione peroxidase; Humans; Immunology; Life Sciences; Membrane Proteins - pharmacology; Mice; Mitochondria; Mitochondrial Proteins; Nuclear transport; Oxidative phosphorylation; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Phosphorylation; Reactive oxygen species; Reactive Oxygen Species - metabolism; Retrograde transport; Therapeutic targets; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - genetics
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-06033-2

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.