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Mitochondrial dysfunction promotes aquaporin expression that controls hydrogen peroxide permeability and ferroptosis.


ABSTRACT: Most anti-cancer agents and radiotherapy exert their therapeutic effects via the production of free radicals. Ferroptosis is a recently described cell death process that is accompanied by iron-dependent lipid peroxidation. Hydrogen peroxide (H2O2) has been reported to induce cell death. However, it remains controversial whether H2O2-induced cell death is ferroptosis. In the present study, we aimed to elucidate the involvement of mitochondria in H2O2-induced ferroptosis and examined the molecules that regulate ferroptosis. We found that one mechanism underlying H2O2-induced cell death is ferroptosis, which occurs soon after H2O2 treatment (within 3 h after H2O2 treatment). We also investigated the involvement of mitochondria in H2O2-induced ferroptosis using mitochondrial DNA-depleted ?0 cells because ?0 cells produce more lipid peroxidation, hydroxyl radicals (OH), and are more sensitive to H2O2 treatment. We found that ?0 cells contain high Fe2+ levels that lead to OH production by H2O2. Further, we observed that aquaporin (AQP) 3, 5, and 8 bind nicotinamide-adenine dinucleotide phosphate oxidase 2 and regulate the permeability of extracellular H2O2, thereby contributing to ferroptosis. Additionally, the role of mitochondria in ferroptosis was investigated using mitochondrial transfer in ?0 cells. When mitochondria were transferred into ?0 cells, the cells exhibited no sensitivity to H2O2-induced cytotoxicity because of decreased Fe2+ levels. Moreover, mitochondrial transfer upregulated the mitochondrial quality control protein prohibitin 2 (PHB2), which contributes to reduced AQP expression. Our findings also revealed the involvement of AQP and PHB2 in ferroptosis. Our results indicate that H2O2 treatment enhances AQP expression, Fe2+ level, and lipid peroxidation, and decrease mitochondrial function by downregulating PHB2, and thus, is a promising modality for effective cancer treatment.

SUBMITTER: Takashi Y 

PROVIDER: S-EPMC7530583 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Mitochondrial dysfunction promotes aquaporin expression that controls hydrogen peroxide permeability and ferroptosis.

Takashi Yuko Y   Tomita Kazuo K   Kuwahara Yoshikazu Y   Roudkenar Mehryar Habibi MH   Roushandeh Amaneh Mohammadi AM   Igarashi Kento K   Nagasawa Taisuke T   Nishitani Yoshihiro Y   Sato Tomoaki T  

Free radical biology & medicine 20201002


Most anti-cancer agents and radiotherapy exert their therapeutic effects via the production of free radicals. Ferroptosis is a recently described cell death process that is accompanied by iron-dependent lipid peroxidation. Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) has been reported to induce cell death. However, it remains controversial whether H<sub>2</sub>O<sub>2</sub>-induced cell death is ferroptosis. In the present study, we aimed to elucidate the involvement of mitochondria in H<sub>2  ...[more]

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