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Activation of ERK–Drp1 signaling promotes hypoxia-induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity
FEBS Open Bio ( IF 2.6 ) Pub Date : 2021-08-17 , DOI: 10.1002/2211-5463.13273
Yuan Yuan 1 , Jingjiong Chen 1 , Xuhua Ge 2 , Jiangshan Deng 1 , Xiaofeng Xu 1 , Yuwu Zhao 1 , Hongmei Wang 1
Affiliation  

Hypoxia is a risk factor for Alzheimer's disease (AD). Besides, mitochondrial fission is increased in response to hypoxia. In this study, we sought to investigate whether hypoxia-induced mitochondrial fission plays a critical role in regulating amyloid-β (Aβ) production. Hypoxia significantly activated extracellular signal-regulated kinase (ERK), increased phosphorylation of dynamin-related protein 1 (Drp1) at serine 616, and decreased phosphorylation of Drp1 at serine 637. Importantly, hypoxia triggered mitochondrial dysfunction, elevated β-secretase 1 (BACE1) and γ-secretase activities, and promoted Aβ accumulation in HEK293 cells transfected with β-amyloid precursor protein (APP) plasmid harboring the Swedish and Indiana familial Alzheimer's disease mutations (APPSwe/Ind HEK293 cells). Then, we investigated whether the ERK inhibitor PD325901 and Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) would attenuate hypoxia-induced mitochondrial fission and Aβ generation in APPSwe/Ind HEK293 cells. PD325901 and Mdivi-1 inhibited phosphorylation of Drp1 at serine 616, resulting in reduced mitochondrial fission under hypoxia. Furthermore, hypoxia-induced mitochondrial dysfunction, BACE1 activation, and Aβ accumulation were downregulated by PD325901 and Mdivi-1. Our data demonstrate that hypoxia induces mitochondrial fission, impairs mitochondrial function, and facilitates Aβ generation. The ERK–Drp1 signaling pathway is partly involved in the hypoxia-induced Aβ generation by regulating mitochondrial fission and BACE1 activity. Therefore, inhibition of hypoxia-induced mitochondrial fission may prevent or slow the progression of AD.

中文翻译:

ERK-Drp1 信号通路的激活通过上调线粒体裂变和 BACE1 活性促进缺氧诱导的 Aβ 积累

缺氧是阿尔茨海默病 (AD) 的危险因素。此外,线粒体裂变响应于缺氧而增加。在这项研究中,我们试图研究缺氧诱导的线粒体裂变是否在调节淀粉样蛋白-β (Aβ) 的产生中起关键作用。缺氧会显着激活细胞外信号调节激酶 (ERK),增加动力相关蛋白 1 (Drp1) 在丝氨酸 616 处的磷酸化,并降低 Drp1 在丝氨酸 637 处的磷酸化。重要的是,缺氧会引发线粒体功能障碍,升高 β-分泌酶 1 (BACE1 ) 和 γ-分泌酶活性,并促进 Aβ 在转染有瑞典和印第安纳家族性阿尔茨海默病突变的 β-淀粉样前体蛋白 (APP) 质粒 (APPSwe/Ind HEK293 细胞) 的 HEK293 细胞中积累。然后,我们研究了 ERK 抑制剂 PD325901 和 Drp1 抑制剂线粒体分裂抑制剂-1 (Mdivi-1) 是否会减弱 APPSwe/Ind HEK293 细胞中缺氧诱导的线粒体裂变和 Aβ 生成。PD325901 和 Mdivi-1 抑制 Drp1 在丝氨酸 616 处的磷酸化,导致缺氧条件下线粒体裂变减少。此外,PD325901 和 Mdivi-1 下调了缺氧诱导的线粒体功能障碍、BACE1 激活和 Aβ 积累。我们的数据表明,缺氧会诱导线粒体裂变,损害线粒体功能,并促进 Aβ 的产生。ERK-Drp1 信号通路通过调节线粒体裂变和 BACE1 活性部分参与缺氧诱导的 Aβ 生成。因此,抑制缺氧诱导的线粒体分裂可以预防或减缓 AD 的进展。
更新日期:2021-10-02
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