Overexpression of PGC-1α Influences Mitochondrial Signal Transduction of Dopaminergic Neurons

Parkinson's disease (PD) is a common neurodegenerative disease in the elderly. Mitochondrial dysfunction plays an important role in the pathogenesis of PD. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is a powerful transcription factor, interacting with multiple transcription factors and widely involving in the regulation of mitochondrial biogenesis, oxidative stress, and other processes. The present study investigated the neuroprotective effects and signal transduction mechanisms of the overexpression of PGC-1 alpha on N-methyl-4-phenylpyridinium ion (MPP+)-induced mitochondrial damage in SH-SY5Y cell, establishing the cell model of overexpression of PGC-1 alpha and the cell model of PD by using adenoviral vectors and MPP+. 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide thiazolyl blue (MTT) assay was used to investigate the effects of MPP+ and adenovirus on the cell viability of SH-SY5Y cells and the cell viability of experimental groups. Western blot and real-time PCR analysis were used to detect the expression of PGC-1 alpha. Flow cytometry and ELISA were used to detect mitochondrial membrane potential and the level of cytochrome C, respectively. The level of intracellular ATP and H2O2 was measured by multifunctional fluorescence microplate. Western blot analysis and real-time PCR were used to observe the expression of estrogen-related receptor alpha (ERR alpha), peroxisome proliferator-activated receptor gamma (PPAR gamma), nuclear respiratory factor (NRF)-1, and NRF-2. Confocal fluorescence analysis was used to observe subcellular localization of PGC-1 alpha in SH-SY5Y cells under the intervention of MPP+. The expression of PGC-1 alpha messenger RNA and protein significantly increased in Adv-PGC-1 alpha + GFP groups, compared with the control and Adv-GFP groups (P < 0.01). The overexpression of PGC-1 alpha could increase mitochondrial membrane potential, reduce the release of mitochondrial cytochrome C, inhibit H2O2 production, and improve the level of ATP in SH-SY5Y cells. The trend of expression of ERR alpha, PPAR gamma, and NRF-1 was more consistent with PGC-1 alpha, the most remarkable change is ERR alpha, but the expression of NRF-2 has no significant changes. Under the gradually increasing concentration of MPP+, microscale PGC-1 alpha gradually appeared in the cytoplasm of SH-SY5Y cells. The overexpression of PGC-1 alpha can inhibit MPP+-induced mitochondrial damage in SH-SY5Y cells, and PGC-1 alpha may realize the neuroprotective effects via the ERR alpha, PPAR gamma, and NRF-1 pathway.