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 Aβ-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 Aβ-mediated mitochondrial dysfunction. The present study investigated the effect of mortalin overexpression on Aβ-induced mPTP activation and ensuing neuronal apoptosis. Mortalin overexpression inhibited mPTP activation and protected SH-SY5Y neurons against Aβ-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 Aβ 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 Aβ-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 Aβ toxicity and defines possible molecular targets for therapeutic intervention.
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