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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 (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 H2 ...[more]

PMID: 33017631

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Project description:Under oxidative stress conditions, mitochondria are the major site for cellular production of reactive oxygen species (ROS) such as superoxide anion and H2O2 that can attack numerous mitochondrial proteins including dihydrolipoamide dehydrogenase (DLDH). While DLDH is known to be vulnerable to oxidative inactivation, the mechanisms have not been clearly elucidated. The present study was therefore designed to investigate the mechanisms of DLDH oxidative inactivation by mitochondrial reactive oxygen species (ROS). Mitochondria, isolated from rat brain, were incubated with mitochondrial respiratory substrates such as pyruvate/malate or succinate in the presence of electron transport chain inhibitors such as rotenone or antimycin A. This is followed by enzyme activity assay and gel-based proteomic analysis. The present study also examined whether ROS-induced DLDH oxidative inactivation could be reversed by reducing reagents such as DTT, cysteine, and glutathione. Results show that DLDH could only be inactivated by complex III- but not complex I-derived ROS; and the accompanying loss of activity due to the inactivation could be restored by cysteine and glutathione, indicating that DLDH oxidative inactivation by complex III-derived ROS was a reversible process. Further studies using catalase indicate that it was H2O2 instead of superoxide anion that was responsible for DLDH inactivation. Moreover, using sulfenic acid-specific labeling techniques in conjunction with two-dimensional Western blot analysis, we show that protein sulfenic acid formation (also known as sulfenation) was associated with the loss of DLDH enzymatic activity observed under our experimental conditions. Additionally, such oxidative modification was shown to be associated with preventing DLDH from further inactivation by the thiol-reactive reagent N-ethylmaleimide. Taken together, the present study provides insights into the mechanisms of DLDH oxidative inactivation by mitochondrial H2O2.

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

Publications

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

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