There is evidence to show the neuroprotective properties of UCPs. UCP2 expression was critical in reducing ROS generation in brain of UCP2-knockout mice, and mice that overexpress human UCP2 have lower dopaminergic cell loss against MPTP toxicity [
42]. UCP2 can reduce mitochondrial ROS by facilitating fatty acid hydroperoxides cycling and proton leak [
43]. Superoxides generated during respiration can induce lipid peroxidation, which in turn activates UCPs to increase proton leak to diminish superoxide production in a negative feedback loop [
44]. Neuronal UCP expression appears to be responsive to oxidative stress in various
in vitro and
in vivo experimental models of PD [
32‐
34]. UCP2 and UCP5 expression were up-regulated in brains of patients after developing ischemic lesions from embolic stroke and multiple infarction [
33]. Similar induction of UCP2 and UCP5 expression was also observed in colonic cells under oxidative stress, demonstrating a potential local feedback mechanism in counteracting oxidative damage and mitochondrial dysfunction [
35]. We observed a time- and dose-dependent induction of UCP2, 4, and 5 expression in human neuronal cells after exposure to MPP
+, the toxic metabolite of MPTP [
32]. MPP
+ specifically inhibits mitochondrial Complex I activity, which impairs oxidative phosphorylation and subsequently causes ATP deficiency and oxidative stress. Neuronal UCP mRNA expression increased with increased MPP
+-induced toxicity. We postulated that these increases in their gene expression served to protect the neurons against MPP
+ toxicity. To explore this hypothesis, we knocked down UCP5 expression by siRNA in SH-SY5Y neuronal cells and found that reduced UCP5 expression exacerbated MPP
+-induced mitochondrial depolarization and induced apoptosis, indicating that UCP5 played a significant role in protecting the neurons against MPP
+-induced toxicity [
45]. This finding was supported by our later study where we stably overexpressed UCP5 expression in these cells, and demonstrated its protective properties [
37]. We found that overexpressing UCP5 could preserve MMP and ATP levels, and suppress oxidative stress induced by MPP
+. Similarly, we demonstrated the neuroprotective properties of UCP4 using SH-SY5Y neuronal cells overexpressing UCP4 under MPP
+ toxicity. We found that increasing UCP4 expression could preserve cellular ATP levels and MMP, which made these neuronal cells more resistant to MPP
+-induced ATP deficiency and oxidative stress. Furthermore, it is interesting to note that UCP2 expression in response to MPP
+-induced mitochondrial dysfunction could be effectively suppressed by overexpressing UCP4, indicating a functional link between UCP2 and UCP4 [
36].