UPRmt activation protects against MPP+-induced toxicity in a cell culture model of Parkinson's disease

Abstract

The pathogenesis of Parkinson's disease (PD) remains elusive, but mitochondrial dysfunction is believed to be one crucial step in its pathogenesis. The mitochondrial unfolded protein response (UPR^mt) is an important mitochondrial quality control strategy that maintains mitochondrial function in response to disturbances of mitochondrial protein homeostasis. Activation of the UPR^mt and the beneficial effect of rescuing mitochondrial proteostasis have been reported in several genetic models of PD. However, the pathogenic relevance of the UPR^mt in idiopathic PD is unknown. The present study examined the link between the UPR^mt and mitochondrial dysfunction in 1-methyl-4-phenylpyridinium (MPP⁺)-treated SH-SY5Y cells. Treatment with MPP ⁺ induced activation of the UPR^mt, reflected by an increase in the expression of UPR^mt-related chaperones, proteases, and transcription mediators. UPR^mt activation that was induced by overexpressing mutant ornithine transcarbamylase significantly reduced the production of mitochondrial reactive oxygen species (ROS) and improved cell survival in SH-SY5Y cells following MPP⁺ treatment. Moreover, the overexpression of activating transcription factor 5 (mammalian UPR^mt transcription factor) conferred protection against MPP⁺-induced ROS production and against cell death in SH-SY5Y cells. Overall, our results demonstrate the beneficial effect of UPR^mt activation in MPP ⁺ -treated cells, shedding new light on the mechanism of mitochondrial dysfunction in the pathogenesis of PD.

Keywords: ATF5; MPP(+); Parkinson's disease; UPR(mt).