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

Abstract

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 γ coactivator 1α (PGC-1α) 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-1α on N-methyl-4-phenylpyridinium ion (MPP(+))-induced mitochondrial damage in SH-SY5Y cell, establishing the cell model of overexpression of PGC-1α 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-1α. 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 α (ERRα), peroxisome proliferator-activated receptor γ (PPARγ), nuclear respiratory factor (NRF)-1, and NRF-2. Confocal fluorescence analysis was used to observe subcellular localization of PGC-1α in SH-SY5Y cells under the intervention of MPP(+). The expression of PGC-1α messenger RNA and protein significantly increased in Adv-PGC-1α + GFP groups, compared with the control and Adv-GFP groups (P < 0.01). The overexpression of PGC-1α 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 ERRα, PPARγ, and NRF-1 was more consistent with PGC-1α, the most remarkable change is ERRα, but the expression of NRF-2 has no significant changes. Under the gradually increasing concentration of MPP(+), microscale PGC-1α gradually appeared in the cytoplasm of SH-SY5Y cells. The overexpression of PGC-1α can inhibit MPP(+)-induced mitochondrial damage in SH-SY5Y cells, and PGC-1α may realize the neuroprotective effects via the ERRα, PPARγ, and NRF-1 pathway.

HO‐1 Is Essential for Tetrahydroxystilbene Glucoside Mediated Mitochondrial Biogenesis and Anti‐Inflammation Process in LPS‐Treated RAW264.7 Macrophages

“…PGC-1 α activated NRF1 and TFAM, which could regulate the nuclear genes encoding proteins associated with mitochondrial respiratory chain and mtDNA replication [13, 19]. COX-I and COX-IV are important members of the mitochondrial respiratory chain.…”

“…In mammalian cells, mitochondrial biogenesis is activated by both physiological and pathological procedures, such as cell division, exercise, calorie restriction, oxidative stress, and inflammation [16–18]. Mitochondrial biogenesis is regulated by a complex network of factors, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α ), nuclear factor-erythroid derived 2-related factor 1 (NRF1), and mitochondrial transcription factor A (TFAM) [19]. These transcription factors and coactivators regulate mitochondrial proteins synthesis and mitochondrial DNA (mtDNA) replication.…”

Mitochondrial Effects of PGC-1alpha Silencing in MPP+ Treated Human SH-SY5Y Neuroblastoma Cells

“…Increased PGC-1α expression could improve dopaminergic neuronal viability and mitochondrial activity in in vivo and in vitro PD models (Mudò et al, 2012; Ferretta et al, 2014; Mäkelä et al, 2016). Our previous work has also suggested that the up-regulation of PGC-1α may have a significant impact on mitochondrial signal transduction by up-regulating the expression of ERRα, NRF-1, NRF-2 and PPARγ (Ye et al, 2016). Meanwhile, PD patients exhibit declining levels of cellular bioenergetic-related gene expression that closely corresponded to the level of PGC-1α (Zheng et al, 2010).…”

Neuropathological characterization of FL-PGC-1α-deficient mice – implications for mitochondrial encephalopathy

“…In a comprehensive study [4], the expression of PGC-1α significantly increased after H2O2 challenge in 10T1/2 cells, which effect was recapitulated by others on C2C12 muscle cells [13]. This is in correspondence with our recent findings of significantly increased PGC-1α mRNA expression in the CNS of mice intoxicated with the neurotoxin 3-nitropropionic acid (3-NP), an irreversible inhibitor of complex II [14], and with a similar finding by others on SH-SY5Y cells using 1-methyl-4-phenylpyridinium (MPP+), an irreversible inhibitor of complex I [15]. Furthermore, RNAi against PGC-1α reduced the baseline expression of Mn-SOD (SOD2), Cu/Zn-SOD (SOD1), and GPX in 10T1/2 cells, whereas the expression of Mn-SOD, Cu/Zn-SOD, and peroxisomal CAT was found reduced in the heart and brain of PGC-1α-deficient mice [4].…”

“…Calling for a potential therapeutic relevance in PD, the overexpression of PGC-1α demonstrated neuroprotection against α-synuclein-induced toxicity in vitro [51,56] and in PGC-1α-deficient mice in vivo [17], against MPP+ [15] and rotenone toxicity in vitro [51], and in a parkin interacting substrate (PARIS) overexpression model of PD in vivo [53]. In line with these, transgenic overexpression and resveratrol-induced activation of PGC-1α (via deacetylation by Sirt-1) both rendered neuroprotection against MPTP toxicity in mice [57].…”