Example：10.1021/acsami.1c06204 or Chem. Rev., 2007, 107, 2411-2502
Activation of ERK–Drp1 signaling promotes hypoxia-induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity FEBS Open Bio (IF2.693), Pub Date : 2021-08-17, DOI: 10.1002/2211-5463.13273 Yuan Yuan, Jingjiong Chen, Xuhua Ge, Jiangshan Deng, Xiaofeng Xu, Yuwu Zhao, Hongmei Wang
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.