Oxidative stress-mediated activation of extracellular signal-regulated kinase contributes to mild cognitive impairment-related mitochondrial dysfunction
| Autor: | John Xi Chen, Xueqi Gan, Russell H. Swerdlow, Honglian Shi, Haiyang Yu, Long Wu, Shengbin Huang, Guangyue Li, Changjia Zhong, Shirley ShiDu Yan |
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| Rok vydání: | 2014 |
| Předmět: |
Male
MFN2 Mitochondrion Biology Mitochondrial Dynamics Biochemistry Cytoplasmic hybrid Article GTP Phosphohydrolases Mitochondrial Proteins Cognition Alzheimer Disease Physiology (medical) mental disorders medicine Humans Cognitive Dysfunction RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Protein Kinase Inhibitors Cells Cultured Aged Flavonoids Membrane Potential Mitochondrial Neurons Neurodegeneration Middle Aged medicine.disease Mitochondria Cell biology Enzyme Activation Oxidative Stress mitochondrial fusion DNAJA3 Female RNA Interference Mitochondrial fission Signal Transduction Abnormal mitochondrial morphology |
| Zdroj: | Free Radical Biology and Medicine. 75:230-240 |
| ISSN: | 0891-5849 |
| DOI: | 10.1016/j.freeradbiomed.2014.07.021 |
| Popis: | Mild cognitive impairment (MCI) occurs during the predementia stage of Alzheimer 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 and mitochondrial dynamic and functional defects in MCI-derived mitochondria. Using a 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 that increased expression levels of mitofusin 2 (Mfn2) are 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 of new therapeutic approaches that improve mitochondrial function in age-related neurodegeneration. |
| Databáze: | OpenAIRE |
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