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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Gan, Xueqi Swerdlow, Russell Howard Hu, Gang Yu, Haiyang Yan, Shirley Shidu Wu, Long Li, Guangyue Zhang, Hongju Wang, Yongfu Chen, John Xi Huang, Shengbin |
| Description | Author Affiliation: Gan X ( Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA); Huang S ( Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA); Wu L ( Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.); Wang Y ( Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.); Hu G ( Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.); Li G ( Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA); Zhang H ( Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.); Yu H ( State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du 610041, China.); Swerdlow RH ( Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160, USA.); Chen JX ( Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 1003, USA.); Yan SS ( Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA. Electronic address: shidu@ku.edu.) |
| 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 (DLP1(K38A)), 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. |
| ISSN | 00063002 |
| Journal | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number | 2 |
| Volume Number | 1842 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2014-02-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Alzheimer Disease Metabolism Extracellular Signal-Regulated MAP Kinases GTP Phosphohydrolases Hybrid Cells Microtubule-Associated Proteins Mitochondria Mitochondrial Proteins Genetics Pathology Antioxidants Pharmacology Immunoblotting Drug Effects Mitochondrial Dynamics Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Models, Biological Mutation Neurons Probucol Quinazolinones RNA Interference Reactive Oxygen Species Signal Transduction Research Support, N.I.H., Extramural Biochemistry |
| Content Type | Text |
| Resource Type | Article |
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