Oxidative stress-mediated activation of extracellular signal-regulated kinase contributes to mild cognitive impairment-related mitochondrial dysfunction.
Oxidative stress-mediated activation of extracellular signal-regulated kinase contributes to mild cognitive impairment-related mitochondrial dysfunction.
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DOI：
10.1016/j.freeradbiomed.2014.07.021
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发表时间：
2014-10
影响因子：
7.4
通讯作者：
Yan, Shirley ShiDu
中科院分区：
文献类型：
--
作者：
Gan, Xueqi;Wu, Long;Huang, Shengbin;Zhong, Changjia;Shi, Honglian;Li, Guangyue;Yu, Haiyang;Swerdlow, Russell Howard;Chen, John Xi;Yan, Shirley ShiDu
关键词：
轻度认知障碍 (MCI) 发生在阿尔茨海默病 (AD) 的痴呆前期，其特征是认知能力下降，通常代表正常认知和 AD 痴呆之间的过渡。其发病机制尚不清楚。在这里，我们展示了 MCI 来源的线粒体中氧化应激、线粒体动态和功能缺陷的直接后果和潜在机制。使用细胞质杂交（cybrid）细胞模型，将来自 MCI 或年龄匹配的非 MCI 受试者的线粒体整合到耗尽内源线粒体 DNA 的人神经元细胞系中，我们评估了线粒体动力学和功能，以及氧化应激在所得 cybrid 系中的作用。我们证明，MCI 来源的线粒体中的氧化应激以及异常的线粒体功能显着诱导了线粒体融合蛋白 2 (Mfn2) 表达水平的增加。抑制氧化应激可挽救 MCI 受损的线粒体融合/裂变平衡，如抑制 Mfn2 表达、减弱异常线粒体形态和分布以及改善线粒体功能。此外，阻断 MCI 相关应激介导的细胞外信号调节激酶 (ERK) 信号激活不仅可以减弱异常的线粒体形态和功能，还可以恢复线粒体裂变和融合平衡，特别是抑制过表达的 Mfn2。我们的研究结果为氧化应激-ERK-Mfn2 信号轴在 MCI 相关线粒体异常中的作用提供了新的见解，表明 MCI 阶段可能是开发新的治疗方法的目标，以改善与年龄相关的神经变性中的线粒体功能。
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.
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