Background: Parkinson’s disease (PD) is one of the most common neurodegenerative diseases with complex etiology in sporadic cases. Accumulating evidence suggests that oxidative stress and defects in mitochondrial dynamics are associated with the pathogenesis of PD. The oxidative stress and mitochondrial dynamics are regulated strictly by peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). We investigated whether acetylation and phosphorylation of PGC-1α contribute to protecting neuronal cell against oxidative stress.

Results: We found that acetylation and phosphorylation mediated the nuclear translocation of PGC-1α protects against oxidative damage. In contrast to the increased nuclear PGC-1α, the cytosolic PGC-1α was decreased upon inhibition of GCN5 acetyltransferase. Similarly to the inhibition of GCN5 acetyltransferase, the increased nuclear PGC-1α and the decreased cytosolic PGC-1α were observed upon p38MAPK and AMPK activation. Briefly, the significantly increased nuclear PGC-1α is regulated either by inhibiting the acetylation of PGC-1α or by the phosphorylating PGC-1α, which results in a reduction in ROS.

Conclusion: PGC-1α protects neuronal cells against MPP+-induced toxicity partially through the acetylation of PGC-1α mediated by GCN5, and mostly through the phosphorylation PGC-1α mediated by p38MAPK or AMPK. Therapeutic reagents activating PGC-1α may be valuable for preventing mitochondrial dysfunction in PD by against oxidative damage.

Methods: With established the 1-methyl-4-phenylpyridinium (MPP+)-induced cell model of PD, the effects of MPP+ and experimental reagents on the cell viability was investigated. The expression of PGC-1α, general control of nucleotide synthesis 5 (GCN5), p38 mitogen-activated protein kinase (p38MAPK) and adenosine monophosphate activated protein kinase (AMPK) were detected by Western blotting and quantitative real-time PCR. The level of reactive oxygen species (ROS) was measured by flow cytometry. All statistical analyses were carried out using one-way ANOVA.