Oxidative stress-mediated activation of extracellular signal-regulated kinase contributes to mild cognitive impairment-related mitochondrial dysfunction
dc.contributor.author | Gan, Xueqi | |
dc.contributor.author | Wu, Long | |
dc.contributor.author | Huang, Shengbin | |
dc.contributor.author | Zhong, Changjia | |
dc.contributor.author | Li, Guangyue | |
dc.contributor.author | Yu, Haiyang | |
dc.contributor.author | Swerdlow, Russell Howard | |
dc.contributor.author | Chen, John Xi | |
dc.contributor.author | Yan, Shirley ShiDu | |
dc.date.accessioned | 2017-03-09T21:50:39Z | |
dc.date.available | 2017-03-09T21:50:39Z | |
dc.date.issued | 2015-10-01 | |
dc.identifier.citation | Gan, Xueqi, Long Wu, Shengbin Huang, Changjia Zhong, Honglian Shi, Guangyue Li, Haiyang Yu, Russell Howard Swerdlow, John Xi Chen, and Shirley Shidu Yan. "Oxidative Stress-mediated Activation of Extracellular Signal-regulated Kinase Contributes to Mild Cognitive Impairment-related Mitochondrial Dysfunction." Free Radical Biology and Medicine 75 (2014): 230-40. | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/23393 | |
dc.description.abstract | Mild cognitive impairment (MCI) occurs during the pre-dementia stage of Alzheimer’s disease (AD) and is characterized by a decline in cognitive abilities that frequently represents a transition between normal cognition and AD dementia. Its pathogenesis is not well understood. Here, we demonstrate the direct consequences and potential mechanisms of oxidative stress, mitochondrial dynamic and functional defects in MCI-derived mitochondria. Using cytoplasmic hybrid (cybrid) cell model in which mitochondria from MCI or age-matched non-MCI subjects were incorporated into a human neuronal cell line depleted of endogenous mitochondrial DNA, we evaluated the mitochondrial dynamics and functions, as well as the role of oxidative stress in the resultant cybrid lines. We demonstrated increased expression levels of mitofusin 2 (Mfn2) is markedly induced by oxidative stress in MCI-derived mitochondria along with aberrant mitochondrial functions. Inhibition of oxidative stress rescues MCI-impaired mitochondrial fusion/fission balance as shown by the suppression of Mfn2 expression, attenuation of abnormal mitochondrial morphology and distribution, and improvement in mitochondrial function. Furthermore, blockade of MCI related stress-mediated activation of extracellular signal-regulated kinase (ERK) signaling not only attenuates aberrant mitochondrial morphology and function but also restores mitochondrial fission and fusion balance, in particular inhibition of overexpressed Mfn2. Our results provide new insights into the role of the oxidative stress-ERK-Mfn2 signal axis in MCI-related mitochondrial abnormalities, indicating that the MCI phase may be targetable for the development new therapeutic approaches that improve mitochondrial function in age-related neurodegeneration. | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
dc.subject | Mitochondrial fission and fusion | en_US |
dc.subject | Mild cognitive impairment | en_US |
dc.subject | Oxidative stress | en_US |
dc.subject | ERK | en_US |
dc.subject | Mfn2 | en_US |
dc.subject | Cybrid cells | en_US |
dc.title | Oxidative stress-mediated activation of extracellular signal-regulated kinase contributes to mild cognitive impairment-related mitochondrial dysfunction | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Yan, Shirley ShiDu | |
kusw.kudepartment | Pharmacology & Toxicology | en_US |
dc.identifier.doi | 10.1016/j.freeradbiomed.2014.07.021 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-1165-1784 | |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.