Involvement of mortalin/GRP75/mthsp70 in the mitochondrial impairments induced by A53T mutant α-synuclein

• A53T α-syn could disrupt mitochondrial dynamics and reduce mortalin expression.
• The knockdown of mortalin attenuated the mitochondrial impairments induced by α-syn.
• Mortalin silencing could reduce mitochondrial translocation of A53T α-syn.
• The reduction of mortalin might play a compensatory role in PD.

Mutations and excessive accumulation of α-synuclein (α-syn) can lead to the degeneration of dopaminergic neurons, indicating a pivotal role of α-syn in the pathogenesis of Parkinson׳s disease (PD). Although how α-syn contributes to PD is still elusive, mitochondrial impairments have been reported to be implicated in. Mortalin, a molecular chaperone mainly located in mitochondria, has been linked to the pathogenesis of PD in recent studies. Moreover, some proteomics studies indicate that mortalin is associated with PD-related proteins, including α-syn. Therefore it is of interest to understand the function of mortalin in the mitochondrial disruption induced by A53T α-syn overexpression. The present study modulated the expression of mortalin and detected the effect of mortalin on the mitochondrial impairments induced by A53T α-syn in SH-SY5Y cells. Our data revealed that A53T α-syn could disrupt mitochondrial dynamics and increase the neuronal susceptibility to neurotoxin rotenone. The expression of mortalin decreased significantly in dopaminergic cells overexpressing A53T α-syn; furthermore, the down-regulation of mortalin could attenuate the disrupted mitochondrial dynamics by reducing α-syn translocation to mitochondria, suggesting that a compensatory mechanism of mortalin might be implicated in the pathogenesis of PD.