Inhibition of mitochondrial permeability transition pore opening is involved in the protective effects of mortalin overexpression against beta-amyloid-induced apoptosis in SH-SY5Y cells

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• 作者：Mingyue Qu ; Zhou Zhou  ; ;   ; ^{lunazhou00@163.com} ;   ; ^{lunazhousci@163.com} ; Chunhai Chen ; Min Li ; Liping Pei ; Ju Yang ; Yuan Wang ; Li Li ; Chuan Liu ; Guangbin Zhang ; Zhengping Yu ; Denggao Wang
• 关键词：Alzheimer's disease ; ¦Â-Amyloid ; Apoptosis ; Mortalin ; Mitochondrial permeability transition ; SH-SY5Y cells
• 刊名：Neuroscience Research
• 出版年：2012
• 出版时间：January 2012
• 年：2012
• 卷：71
• 期：2
• 页码：94-102
• 全文大小：926 K

文摘

Mortalin (mtHsp70) is a mitochondrial heat shock protein critical for maintaining the functional integrity of mitochondrial proteins. Our previous study demonstrated that mortalin overexpression protected against A¦Â-induced neurotoxicity through a mitochondria-dependent mechanism, but the molecular details remained unclear. Recent biochemical studies implicate opening of the mitochondrial permeability transition pore (mPTP) in A¦Â-mediated mitochondrial dysfunction. The present study investigated the effect of mortalin overexpression on A¦Â-induced mPTP activation and ensuing neuronal apoptosis. Mortalin overexpression inhibited mPTP activation and protected SH-SY5Y neurons against A¦Â-induced apoptosis. Compared to controls, neurons overexpressing mortalin also demonstrated superior intracellular free calcium regulation, lower mitochondrial reactive oxygen species generation, and decreased Bax/Bcl-2 ratios in response to A¦Â treatment. Mortalin overexpression suppressed activation of the mitochondrial apoptotic cascade as demonstrated by inhibition of cytochrome c release and caspase-3 activation. Our results indicate that the cytoprotective efficacy of mortalin under A¦Â-induced stress is mediated, at least in part, by inhibition of mPTP opening. Demonstration of the neuroprotective action of mortalin provides additional insights into the pathogenic mechanisms of A¦Â toxicity and defines possible molecular targets for therapeutic intervention.