NDLI: Oxidative stress-mediated activation of extracellular signal-regulated kinase contributes to mild cognitive impairment-related mitochondrial dysfunction

Content Provider	PubMed Central
Author	Gan, Xueqi Long, Wu Huang, Shengbin Zhong, Changjia Li, Guangyue Yu, Haiyang Swerdlow, Russell Howard Chen, John Xi Yan, Shirley Shidu
Copyright Year	2014
Abstract	Mild cognitive impairment (MCI) occurs during the pre-dementia stage of Alzheimer’s 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, mitochondrial dynamic and functional defects in MCI-derived mitochondria. Using 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 increased expression levels of mitofusin 2 (Mfn2) is 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 new therapeutic approaches that improve mitochondrial function in age-related neurodegeneration.
Related Links	http://dx.doi.org/10.1016/j.freeradbiomed.2014.07.021
Ending Page	240
Page Count	11
Starting Page	230
File Format	PDF
ISSN	08915849
e-ISSN	18734596
Journal	Free radical biology & medicine
Volume Number	75
Language	English
Publisher Date	2014-10-01
Access Restriction	Open
Subject Keyword	Physiology (medical) Biochemistry Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology (medical) Biochemistry

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