NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases.
NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases.
复制标题
DOI：
10.1016/j.redox.2021.101947
复制
发表时间：
2021-05
期刊：
影响因子：
11.4
通讯作者：
Moon JS
中科院分区：
文献类型：
--
作者：
Park MW;Cha HW;Kim J;Kim JH;Yang H;Yoon S;Boonpraman N;Yi SS;Yoo ID;Moon JS
氧化应激与阿尔茨海默病（Alzheimer's disease，AD）的发病机制有关。线粒体功能障碍与AD期间神经毒性中的氧化应激和活性氧（ROS）有关。线粒体代谢受损与AD脑损伤中的线粒体功能障碍有关。虽然NADPH氧化酶4（NOX 4）（ROS的主要来源）在脑损伤中的作用已被确定，但NOX 4调节AD中星形胶质细胞的铁凋亡的机制仍不清楚。在这里，我们表明，NOX 4的蛋白水平显着升高，在受损的星形胶质细胞的AD患者和APP/PS1双转基因小鼠模型的AD。4-羟基壬烯醛（4-HNE）和丙二醛（MDA），氧化应激诱导的脂质过氧化的标志物的水平也显着升高，在受损的星形胶质细胞AD患者和小鼠AD。我们证明，NOX 4的过表达显着增加线粒体代谢的损害，通过抑制线粒体呼吸和ATP的生产，通过减少五个蛋白质复合物在人星形胶质细胞线粒体ETC。此外，NOX 4的升高通过线粒体活性氧（mtROS）的产生、线粒体断裂和人类星形胶质细胞细胞抗氧化过程的抑制来诱导氧化应激。此外，NOX 4的升高通过激活人星形胶质细胞中氧化应激诱导的脂质过氧化增加了铁蛋白分解依赖的细胞毒性。这些结果表明，NOX 4促进铁凋亡的星形胶质细胞的氧化应激诱导的脂质过氧化损伤的线粒体代谢在AD。在人类和小鼠AD的受损星形胶质细胞中，NOX 4的水平升高。人和小鼠AD损伤的星形胶质细胞中4-HNE和MDA水平升高。NOX 4通过损伤人星形胶质细胞线粒体诱导氧化应激NOX 4通过氧化应激促进人星形胶质细胞中的铁凋亡。
Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction is linked to oxidative stress and reactive oxygen species (ROS) in neurotoxicity during AD. Impaired mitochondrial metabolism has been associated with mitochondrial dysfunction in brain damage of AD. While the role of NADPH oxidase 4 (NOX4), a major source of ROS, has been identified in brain damage, the mechanism by which NOX4 regulates ferroptosis of astrocytes in AD remains unclear. Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD. The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD. We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes. Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes. Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes. These results suggest that NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in AD. The levels of NOX4 were elevated in impaired astrocytes of human and mouse AD. The levels of 4-HNE and MDA were elevated in impaired astrocytes of human and mouse AD. NOX4 induces oxidative stress by the impairment of mitochondria in human astrocytes. NOX4 promotes ferroptosis by oxidative stress in human astrocytes.
登录
查看更多内容
DOI：
10.3233/jad-170829
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
de la Monte SM;Tong M;Wands JR
通讯作者：
Wands JR
影响因子：
11.4
作者：
Hardas, Santa S.;Sultana, Rukhsana;Clark, Amy M.;Beckett, Tina L.;Szweda, Luke I.;Murphy, M. Paul;Butterfield, D. Allan
通讯作者：
Butterfield, D. Allan
影响因子：
5.3
作者：
Abramov, AY;Canevari, L;Duchen, MR
通讯作者：
Duchen, MR
影响因子：
7
作者：
Fusco, Roberta;Cordaro, Marika;Di Paola, Rosanna
通讯作者：
Di Paola, Rosanna
影响因子：
6.1
作者：
Bruce-Keller, Annadora J.;Gupta, Sunita;Knight, Alecia G.;Beckett, Tina L.;McMullen, Jessica M.;Davis, Paulina R.;Murphy, M. Paul;Van Eldik, Linda J.;St Clair, Daret;Keller, Jeffrey N.
通讯作者：
Keller, Jeffrey N.