Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity. Issue 10 (27th August 2021)

• Record Type: Journal Article
• Authors: Yuan, Yuan; Chen, Jingjiong; Ge, Xuhua; Deng, Jiangshan; Xu, Xiaofeng; Zhao, Yuwu; Wang, Hongmei
• Is Part Of: FEBS open bio. Volume 11:Issue 10(2021)
• Page Start: 2740
• Page End: 2755
• Publication Date: 2021-08-27
• Subjects: Alzheimer's disease -- BACE1 -- ERK -- hypoxia -- mitochondrial fission; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.13273
• Languages: English
• ISSNs: 2211-5463

Abstract

Abstract : 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. Abstract : Hypoxia is a risk factor for Alzheimer's disease. However, whether hypoxia‐induced mitochondrial fission plays a critical role in the regulation of amyloid‐β (Aβ) accumulation has not yet been investigated. In the current study, we show that the ERK/Drp1 signaling pathway is partly involved in regulating mitochondrial fission and Aβ generation under hypoxia.