Regulation of PPAR-γ coactivator-1α and its implication in mitochondrial function and neurodegenerative diseases

Peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, interacts with numerous transcription factors implicated in a wide spectrum of biological responses. It has been identified as a key player in the transcriptional regulation of many mitochondrial components. The activity of PGC1-α is regulated at multiple levels, such as gene expression, transcriptional, post-transcriptional, and post-translational modification. The purpose of this review is to highlight the data supporting PGC1-α-mediated regulation by transcriptional and post-translational modification. We summarize the mechanisms involved in PGC1-α regulation by phosphorylation (AMPK, p38 MAPK, Akt, and GSK3β), acetylation (GCN5, p300, and SRCC), and ubiquitination (E3-ubiquitin ligase). Moreover, the review focuses on the multidomain structure of PGC1-α, its expression in the brain, and the importance of PGC1-α-mediated mitochondrial functions.

Mitochondrial dysfunction and impaired energy metabolism are key characteristics of neurodegenerative diseases like Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis, and multiple sclerosis. It is associated with reduced PGC1-α expression or activity, resulting in an imbalance in the maintenance of mitochondrial dynamics. In this backdrop, we additionally provide a comprehensive overview of the implication of PGC1-α in the pathogenesis of neurodegenerative disease. Overall, PGC1-α acts as a potential target for therapies to reduce mitochondrial dysfunction associated with neurodegenerative diseases and aid in neuroprotection.