2. Academic Validation
  3. Identification of Frataxin as a regulator of ferroptosis

Identification of Frataxin as a regulator of ferroptosis

  • Redox Biol. 2020 May:32:101483. doi: 10.1016/j.redox.2020.101483.
Jing Du 1,  Yi Zhou 2,  Yanchun Li 3,  Jun Xia 1,  Yongjian Chen 1,  Sufeng Chen 1,  Xin Wang 4,  Weidong Sun 5,  Tongtong Wang 6,  Xueying Ren 1,  Xu Wang 7,  Yihan An 8,  Kang Lu 8,  Wanye Hu 8,  Siyuan Huang 3,  Jianghui Li 7,  Xiangmin Tong 9,  Ying Wang 10
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
  • 2 The Second Clinical Medical School of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China; Department of Wangjiangshan, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
  • 3 The Second Clinical Medical School of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
  • 4 Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
  • 5 Department of Hematology, Shaoxing Central Hospital, Shaoxing, Zhejiang, 312030, China; Bengbu Medical College, Bengbu, Anhui, 233000, China.
  • 6 Department of Wangjiangshan, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
  • 7 School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 8 Bengbu Medical College, Bengbu, Anhui, 233000, China.
  • 9 Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Phase I Clinical Research Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; The Second Clinical Medical School of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China; Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Bengbu Medical College, Bengbu, Anhui, 233000, China. Electronic address: tongxiangming@hmc.edu.cn.
  • 10 Phase I Clinical Research Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Bengbu Medical College, Bengbu, Anhui, 233000, China. Electronic address: wangying@hmc.edu.cn.
PMID: 32169822 DOI: 10.1016/j.redox.2020.101483
Abstract

Ferroptosis is a newly discovered form of non-apoptotic regulated cell death and is characterized by iron-dependent and lipid peroxidation. Due to the enhanced dependence on iron in Cancer cells, induction of Ferroptosis is becoming a promising therapeutic strategy. However, the precise underlying molecular mechanism and regulation process of Ferroptosis remains largely unknown. In the present study, we demonstrate that the protein Frataxin (FXN) is a key regulator of Ferroptosis by modulating iron homeostasis and mitochondrial function. Suppression of FXN expression specifically repressed the proliferation, destroyed mitochondrial morphology, impeded Fe-S cluster assembly and activated iron starvation stress. Moreover, suppression of FXN expression significantly enhanced erastin-induced cell death through accelerating free iron accumulation, lipid peroxidation and resulted in dramatic mitochondria morphological damage including enhanced fragmentation and vanished cristae. In addition, this type of cell death was confirmed to be Ferroptosis, since it could be pharmacologically restored by ferroptotic inhibitor Fer-1 or GSH, but not by inhibitors of Apoptosis, necrosis. Vice versa, enforced expression of FXN blocked iron starvation response and erastin-induced Ferroptosis. More importantly, pharmacological or genetic blocking the signal of iron starvation could completely restore the resistance to Ferroptosis in FXN knockdown cells and xenograft graft in vivo. This paper suggests that FXN is a novel Ferroptosis modulator, as well as a potential provided target to improve the antitumor activity based on Ferroptosis.

Keywords

Ferroptosis; Frataxin; Iron-sulfur cluster; Mitochondria.

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