Fig. 6.

Schematic demonstrating Ca⁺² and potentially Fe⁺² uptake by L-type Ca⁺² channel in dopaminergic neurons [156] and the regulatory function of DJ-1 in attenuating mitochondria oxidant stress via the mitochondrial uncoupling proteins (UCP4 and UCP5). The release of Ca⁺² from the endoplasmic reticulum (ER) into the mitochondrion is facilitated by the complex formed between the endoplasmic reticulum Ca⁺² channel, inositol 1,4,5-triphosphate receptor (IP3R), and VDAC1-mediated by the mitochondrial chaperone, glucose-regulated protein 75 (GRP75) [449]. The influx of Ca⁺² during pacemaking can lead to a high metabolic load resulting in the accumulation of ROS via oxidative phosphorylation [447]. In non-parkinsonian neurons, DJ-1 increases UCP4 and UCP5 expression, these uncoupled proteins play an important role in protecting the mitochondrion against stress and damage by suppressing ROS production [447]. Both UPC4 and UPC5 may also inhibit ROS-mediated cytochrome c release and its neuronal apoptotic pathways [63].