Show simple item record

dc.contributor.authorGan, Xueqi
dc.contributor.authorHuang, Shengbin
dc.contributor.authorWu, Long
dc.contributor.authorWang, Yongfu
dc.contributor.authorHu, Gang
dc.contributor.authorLi, Guangyue
dc.contributor.authorZhang, Hongju
dc.contributor.authorYu, Haiyang
dc.contributor.authorSwerdlow, Russell Howard
dc.contributor.authorChen, John Xi
dc.contributor.authorYan, Shirley ShiDu
dc.date.accessioned2017-02-08T19:16:10Z
dc.date.available2017-02-08T19:16:10Z
dc.date.issued2014-02
dc.identifier.citationGan 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.urihttp://hdl.handle.net/1808/22728
dc.description.abstractMitochondrial 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.publisherAssociation of American Medical Collegesen_US
dc.rightsThis 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.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMitochondrial fission and fusionen_US
dc.subjectAlzheimer's diseaseen_US
dc.subjectCybrid cellsen_US
dc.subjectERKen_US
dc.subjectDLP1en_US
dc.titleInhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer's disease cybrid cellen_US
dc.typeArticleen_US
kusw.kuauthorGan, Xueqi
kusw.kuauthorHuang, Shengbin
kusw.kuauthorWu, Long
kusw.kuauthorWang, Yongfu
kusw.kuauthorHu, Gang
kusw.kuauthorLi, Guangyue
kusw.kuauthorZhang, Hongju
kusw.kuauthorYan, Shirley Shidu
kusw.kudepartmentPharmacology and Toxicologyen_US
dc.identifier.doi10.1016/j.bbadis.2013.11.009en_US
dc.identifier.orcidhttps://orcid.org/0000-0003-3499-0586 https://orcid.org/0000-0003-1165-1784
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.rights.accessrightsopenAccess


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

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.
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.