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Identification of Frataxin as a regulator of ferroptosis

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 m...

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Autores principales: Du, Jing, Zhou, Yi, Li, Yanchun, Xia, Jun, Chen, Yongjian, Chen, Sufeng, Wang, Xin, Sun, Weidong, Wang, Tongtong, Ren, Xueying, Wang, Xu, An, Yihan, Lu, Kang, Hu, Wanye, Huang, Siyuan, Li, Jianghui, Tong, Xiangmin, Wang, Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068686/
https://www.ncbi.nlm.nih.gov/pubmed/32169822
http://dx.doi.org/10.1016/j.redox.2020.101483
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author Du, Jing
Zhou, Yi
Li, Yanchun
Xia, Jun
Chen, Yongjian
Chen, Sufeng
Wang, Xin
Sun, Weidong
Wang, Tongtong
Ren, Xueying
Wang, Xu
An, Yihan
Lu, Kang
Hu, Wanye
Huang, Siyuan
Li, Jianghui
Tong, Xiangmin
Wang, Ying
author_facet Du, Jing
Zhou, Yi
Li, Yanchun
Xia, Jun
Chen, Yongjian
Chen, Sufeng
Wang, Xin
Sun, Weidong
Wang, Tongtong
Ren, Xueying
Wang, Xu
An, Yihan
Lu, Kang
Hu, Wanye
Huang, Siyuan
Li, Jianghui
Tong, Xiangmin
Wang, Ying
author_sort Du, Jing
collection PubMed
description 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.
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spelling pubmed-70686862020-03-18 Identification of Frataxin as a regulator of ferroptosis Du, Jing Zhou, Yi Li, Yanchun Xia, Jun Chen, Yongjian Chen, Sufeng Wang, Xin Sun, Weidong Wang, Tongtong Ren, Xueying Wang, Xu An, Yihan Lu, Kang Hu, Wanye Huang, Siyuan Li, Jianghui Tong, Xiangmin Wang, Ying Redox Biol Research Paper 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. Elsevier 2020-03-02 /pmc/articles/PMC7068686/ /pubmed/32169822 http://dx.doi.org/10.1016/j.redox.2020.101483 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Du, Jing
Zhou, Yi
Li, Yanchun
Xia, Jun
Chen, Yongjian
Chen, Sufeng
Wang, Xin
Sun, Weidong
Wang, Tongtong
Ren, Xueying
Wang, Xu
An, Yihan
Lu, Kang
Hu, Wanye
Huang, Siyuan
Li, Jianghui
Tong, Xiangmin
Wang, Ying
Identification of Frataxin as a regulator of ferroptosis
title Identification of Frataxin as a regulator of ferroptosis
title_full Identification of Frataxin as a regulator of ferroptosis
title_fullStr Identification of Frataxin as a regulator of ferroptosis
title_full_unstemmed Identification of Frataxin as a regulator of ferroptosis
title_short Identification of Frataxin as a regulator of ferroptosis
title_sort identification of frataxin as a regulator of ferroptosis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068686/
https://www.ncbi.nlm.nih.gov/pubmed/32169822
http://dx.doi.org/10.1016/j.redox.2020.101483
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