Mitochondrial dysfunction promotes aquaporin expression that controls hydrogen peroxide permeability and ferroptosis.
Mitochondrial dysfunction promotes aquaporin expression that controls hydrogen peroxide permeability and ferroptosis.
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DOI：
10.1016/j.freeradbiomed.2020.09.027
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发表时间：
2020-12
影响因子：
7.4
通讯作者：
Sato T
中科院分区：
文献类型：
--
作者：
Takashi Y;Tomita K;Kuwahara Y;Roudkenar MH;Roushandeh AM;Igarashi K;Nagasawa T;Nishitani Y;Sato T
大多数抗癌剂和放射疗法通过产生自由基发挥其治疗作用。铁凋亡是最近描述的细胞死亡过程，伴随着铁依赖性脂质过氧化。过氧化氢（H2O2）可诱导细胞死亡。然而，H2O2诱导的细胞死亡是否为铁凋亡仍存在争议。在本研究中，我们的目的是阐明线粒体参与H2O2诱导的铁凋亡，并检查调节铁凋亡的分子。我们发现，H2O2诱导的细胞死亡的一个机制是铁凋亡，这发生后不久H2O2处理（H2O2处理后3小时内）。我们还使用线粒体DNA缺失的ρ0细胞研究了线粒体在H2O2诱导的铁凋亡中的参与，因为ρ0细胞产生更多的脂质过氧化和羟基自由基（·OH），并且对H2O2处理更敏感。我们发现ρ0细胞含有高水平的Fe 2+，导致H2O2产生·OH。此外，我们观察到水通道蛋白（AQP）3，5和8结合烟酰胺腺嘌呤二核苷酸磷酸氧化酶2和调节细胞外H2O2的渗透性，从而有助于铁凋亡。此外，在ρ0细胞中使用线粒体转移研究线粒体在铁凋亡中的作用。当线粒体转移到ρ0细胞中时，由于Fe 2+水平降低，细胞对H2O2诱导的细胞毒性不敏感。此外，线粒体转移上调线粒体质量控制蛋白抑制素2（PHB2），这有助于减少AQP表达。我们的研究结果还表明，AQP和PHB2参与了铁下垂。我们的研究结果表明，H2O2处理增强AQP表达，Fe2+水平，脂质过氧化，并通过下调PHB2降低线粒体功能，因此，是一种有前途的有效的癌症治疗方式。
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 ρ0 cells because ρ0 cells produce more lipid peroxidation, hydroxyl radicals (•OH), and are more sensitive to H2O2 treatment. We found that ρ0 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 ρ0 cells. When mitochondria were transferred into ρ0 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.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
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