Mortalin overexpression attenuates beta-amyloid-induced neurotoxicity in SH-SY5Y cells

Amyloid-beta peptide (Aβ) is shown to be toxic to the mitochondria and implicates this organelle in the pathogenesis of Alzheimer's disease. Previous studies suggest that targeting mitochondria for protection may be a useful strategy to reduce Aβ-induced neurotoxicity. Mortalin is the mitochondrial located member of the heat shock protein 70 family, which serves as a major mitochondrial molecular chaperone and plays a key role in mitochondrial import of proteins. Several studies have demonstrated the protective potential of Hsp75 overexpression against apoptosis induced by various forms of stresses. To investigate whether mortalin overexpression could provide protective effects on Aβ toxicity, SH-SY5Y cells were used to transfect human mortalin gene and then treated with Aβ1–42 for 24 h. It is found that overexpression of mortalin efficiently attenuated Aβ1–42-induced cell viability damage and apoptosis. Additionally, inhibition of mortalin expression by mortalin-specific siRNA oligonucleotides sensitized SH-SY5Y cells to Aβ1–42-induced neurotoxicity. Furthermore, mortalin overexpression significantly inhibited the Aβ1–42-induced depolarization of mitochondrial membrane potential, reversed the Aβ1–42-induced reduction in cytochrome c oxidase activity and ATP generation, and suppressed the Aβ1–42-induced reactive oxygen species accumulation and lipid peroxidation. Together, our results suggest that mortalin can afford protection against Aβ1–42-induced neurotoxicity in SH-SY5Y cells. These beneficial effects of mortalin overexpression may be attributable to its roles in maintaining mitochondrial function and reducing oxidative stress.

Research Highlights
► Overexpression of mortalin efficiently attenuates Aβ1–42-induced neurotoxicity in SH-SY5Y cells.
► Silencing mortalin expression sensitizes SH-SY5Y cells to Aβ1–42-induced neurotoxicity.
► Mortalin overexpression significantly inhibits Aβ1–42-induced mitochondrial dysfunction and oxidative stress.