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Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity

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 a...

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Autores principales: Yuan, Yuan, Chen, Jingjiong, Ge, Xuhua, Deng, Jiangshan, Xu, Xiaofeng, Zhao, Yuwu, Wang, Hongmei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487051/
https://www.ncbi.nlm.nih.gov/pubmed/34403210
http://dx.doi.org/10.1002/2211-5463.13273
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author Yuan, Yuan
Chen, Jingjiong
Ge, Xuhua
Deng, Jiangshan
Xu, Xiaofeng
Zhao, Yuwu
Wang, Hongmei
author_facet Yuan, Yuan
Chen, Jingjiong
Ge, Xuhua
Deng, Jiangshan
Xu, Xiaofeng
Zhao, Yuwu
Wang, Hongmei
author_sort Yuan, Yuan
collection PubMed
description 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.
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spelling pubmed-84870512021-10-07 Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity Yuan, Yuan Chen, Jingjiong Ge, Xuhua Deng, Jiangshan Xu, Xiaofeng Zhao, Yuwu Wang, Hongmei FEBS Open Bio Research Articles 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. John Wiley and Sons Inc. 2021-08-27 /pmc/articles/PMC8487051/ /pubmed/34403210 http://dx.doi.org/10.1002/2211-5463.13273 Text en © 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Yuan, Yuan
Chen, Jingjiong
Ge, Xuhua
Deng, Jiangshan
Xu, Xiaofeng
Zhao, Yuwu
Wang, Hongmei
Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity
title Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity
title_full Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity
title_fullStr Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity
title_full_unstemmed Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity
title_short Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity
title_sort activation of erk–drp1 signaling promotes hypoxia‐induced aβ accumulation by upregulating mitochondrial fission and bace1 activity
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487051/
https://www.ncbi.nlm.nih.gov/pubmed/34403210
http://dx.doi.org/10.1002/2211-5463.13273
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