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Inhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer's disease cybrid cell
dc.contributor.author | Gan, Xueqi | |
dc.contributor.author | Huang, Shengbin | |
dc.contributor.author | Wu, Long | |
dc.contributor.author | Wang, Yongfu | |
dc.contributor.author | Hu, Gang | |
dc.contributor.author | Li, Guangyue | |
dc.contributor.author | Zhang, Hongju | |
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 | 2017-02-08T19:16:10Z | |
dc.date.available | 2017-02-08T19:16:10Z | |
dc.date.issued | 2014-02 | |
dc.identifier.citation | Gan X, Huang S, Wu L, et al. Inhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer’s disease cybrid cell. Biochimica et biophysica acta. 2014;1842(2):220-231. doi:10.1016/j.bbadis.2013.11.009. | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/22728 | |
dc.description.abstract | Mitochondrial dysfunction is an early pathological feature of Alzheimer’s disease (AD). The underlying mechanisms and strategies to repair it remain unclear. Here, we demonstrate for the first time the direct consequences and potential mechanisms of mitochondrial functional defects associated with abnormal mitochondrial dynamics in AD. Using cytoplasmic hybrid (cybrid) neurons with incorporated platelet mitochondria from AD and age-matched non-AD human subjects into mitochondrial DNA (mtDNA)-depleted neuronal cells, we observed that AD cybrid cells had significant changes in morphology and function; such changes associate with altered expression and distribution of dynamin-like protein (DLP1) and mitofusin 2 (Mfn2). Treatment with antioxidant protects against AD mitochondria-induced extracellular signal-regulated kinase (ERK) activation and mitochondrial fission-fusion imbalances. Notably, inhibition of ERK activation not only attenuates aberrant mitochondrial morphology and function but also restores the mitochondrial fission and fusion balance. These effects suggest a role of oxidative stress-mediated ERK signal transduction in modulation of mitochondrial fission and fusion events. Further, blockade of the mitochondrial fission protein DLP1 by a genetic manipulation with a dominant negative DLP1 (DLP1K38A), its expression with siRNA-DLP1, or inhibition of mitochondrial division with mdivi-1 attenuates mitochondrial functional defects observed in AD cybrid cells. Our results provide new insights into mitochondrial dysfunction resulting from changes in the ERK-fission/fusion (DLP1) machinery and signaling pathway. The protective effect of mdivi-1 and inhibition of ERK signaling on maintenance of normal mitochondrial structure and function holds promise as a potential novel therapeutic strategy for AD. | en_US |
dc.publisher | Association of American Medical Colleges | 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/4.0/ | |
dc.subject | Mitochondrial fission and fusion | en_US |
dc.subject | Alzheimer's disease | en_US |
dc.subject | Cybrid cells | en_US |
dc.subject | ERK | en_US |
dc.subject | DLP1 | en_US |
dc.title | Inhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer's disease cybrid cell | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Gan, Xueqi | |
kusw.kuauthor | Huang, Shengbin | |
kusw.kuauthor | Wu, Long | |
kusw.kuauthor | Wang, Yongfu | |
kusw.kuauthor | Hu, Gang | |
kusw.kuauthor | Li, Guangyue | |
kusw.kuauthor | Zhang, Hongju | |
kusw.kuauthor | Yan, Shirley Shidu | |
kusw.kudepartment | Pharmacology and Toxicology | en_US |
dc.identifier.doi | 10.1016/j.bbadis.2013.11.009 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-3499-0586 https://orcid.org/0000-0003-1165-1784 | |
kusw.oaversion | Scholarly/refereed, publisher version | 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.