Inhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer's disease cybrid cell
| Autor: | Russell H. Swerdlow, Hongju Zhang, Yongfu Wang, John Xi Chen, Guangyue Li, Haiyang Yu, Long Wu, Shirley ShiDu Yan, Shengbin Huang, Xueqi Gan, Gang Hu |
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| Rok vydání: | 2014 |
| Předmět: |
Dynamins
Male DLP1 Mitochondrial DNA Immunoblotting MFN2 Hybrid Cells Mitochondrion Biology Mitochondrial Dynamics Models Biological Cytoplasmic hybrid Article Antioxidants GTP Phosphohydrolases Mitochondrial Proteins Mitofusin-2 Alzheimer Disease Humans Extracellular Signal-Regulated MAP Kinases Molecular Biology Aged Quinazolinones Aged 80 and over Mitogen-Activated Protein Kinase 1 Neurons Mitogen-Activated Protein Kinase 3 Middle Aged Alzheimer's disease Mitochondria Cell biology ERK Probucol Cybrid cells mitochondrial fusion Mitochondrial fission and fusion Mutation DNAJA3 Molecular Medicine Female RNA Interference Mitochondrial fission Reactive Oxygen Species Microtubule-Associated Proteins Signal Transduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1842:220-231 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2013.11.009 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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