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

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 ₂ O ₂ ) has been reported to induce cell death. However, it remains controversial whether H ₂ O ₂ -induced cell death is ferroptosis. In the present study, we aimed to elucidate the involvement of mitochondria in H ₂ O ₂ -induced ferroptosis and examined the molecules that regulate ferroptosis. We found that one mechanism underlying H ₂ O ₂ -induced cell death is ferroptosis, which occurs soon after H ₂ O ₂ treatment (within 3 h after H ₂ O ₂ treatment). We also investigated the involvement of mitochondria in H ₂ O ₂ -induced ferroptosis using mitochondrial DNA-depleted ρ ⁰ cells because ρ ⁰ cells produce more lipid peroxidation, hydroxyl radicals ( ^• OH), and are more sensitive to H ₂ O ₂ treatment. We found that ρ ⁰ cells contain high Fe ²⁺ levels that lead to ^• OH production by H ₂ O ₂ . Further, we observed that aquaporin (AQP) 3, 5, and 8 bind nicotinamide-adenine dinucleotide phosphate oxidase 2 and regulate the permeability of extracellular H ₂ O ₂ , thereby contributing to ferroptosis. Additionally, the role of mitochondria in ferroptosis was investigated using mitochondrial transfer in ρ ⁰ cells. When mitochondria were transferred into ρ ⁰ cells, the cells exhibited no sensitivity to H ₂ O ₂ -induced cytotoxicity because of decreased Fe ²⁺ 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 H ₂ O ₂ treatment enhances AQP expression, Fe ²⁺ level, and lipid peroxidation, and decrease mitochondrial function by downregulating PHB2, and thus, is a promising modality for effective cancer treatment.
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