Identification of Frataxin as a regulator of ferroptosis

Redox Biology

Xueying Ren¹  Yanchun Li²  Siyuan Huang³  Wanye Hu³  Jianghui Li³  Weidong Sun⁴  Tongtong Wang⁵  Jing Du⁶  Xin Wang⁶  Sufeng Chen⁶  Yongjian Chen⁶  Yihan An⁶  Xu Wang⁷  Kang Lu⁸  Ying Wang⁸  Jun Xia⁹  Yi Zhou⁹  Xiangmin Tong⁹ 

[1] Bengbu Medical College, Bengbu, Anhui, 233000, China;Department of Wangjiangshan, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China;Bengbu Medical College, Bengbu, Anhui, 233000, China;Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China;Department of Hematology, Shaoxing Central Hospital, Shaoxing, Zhejiang, 312030, China;Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China;Department of Wangjiangshan, 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;The Second Clinical Medical School of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China;

关键词: Ferroptosis;    Frataxin;    Iron-sulfur cluster;    Mitochondria;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown