2. Academic Validation
  3. Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer

Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer

  • Cell Death Dis. 2025 Apr 5;16(1):254. doi: 10.1038/s41419-025-07510-6.
Ru Deng # 1 2 3 4,  Lingyi Fu # 1 2 3,  Haoyu Liang # 1 2 3,  Xixiong Ai 5,  Fangyi Liu 1 2 3,  Nai Li 1 2 3,  Liyan Wu 1 2 3,  Shuo Li 1 2 3,  Xia Yang 1 2 3,  Yansong Lin 1 2 3,  Yuhua Huang 6 7 8,  Jingping Yun 9 10 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4 Department of Radiation Oncology, Peking University Shenzhen Hospital, Shenzhen, China.
  • 5 Reproductive Medicine Center, The Affiliated Shenzhen Maternity and Child Healthcare Hospital of the South Medical University, Shenzhen, Guangdong, China.
  • 6 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. huangyh@sysucc.org.cn.
  • 7 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China. huangyh@sysucc.org.cn.
  • 8 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. huangyh@sysucc.org.cn.
  • 9 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. yunjp@sysucc.org.cn.
  • 10 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China. yunjp@sysucc.org.cn.
  • 11 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. yunjp@sysucc.org.cn.
  • # Contributed equally.
PMID: 40185704 DOI: 10.1038/s41419-025-07510-6
Abstract

Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial Ferroptosis defense systems are Glutathione Peroxidase 4 (GPX4) and Dihydroorotate Dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial Ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes Ferroptosis across GPX4 low-expression Cancer cells. However, in GPX4 high expression Cancer cells, the MCI inhibitor did not induce Ferroptosis, but increased cell sensitivity to Ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells Ferroptosis induced by MCI inhibitors but also confers cellular protection against Ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced Ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial Ferroptosis, but independently of cytosolically localized GPX4 or Ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce Ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a Ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting Ferroptosis in Cancer treatment.

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