Deciphering the PGC-1α-TFAM Axis in Parkinson's Disease (PD) - A Mechanism Approach Targeting Therapeutics for PD

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in dopamine depletion and impaired motor function. Growing evidence implicates mitochondrial dysfunction as a central driver of PD pathogenesis with many PD-associated genes and proteins localized are localized near mitochondria and they also have major functions in proper functioning of mitochondria. Among mitochondrial regulators, the transcriptional co-activator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) orchestrates oxidative stress response, mitochondrial biogenesis and inflammatory pathways whereas mitochondrial transcription factor A (TFAM) is essential for maintaining mitochondrial DNA (mtDNA) integrity and copy number variations. Dysregulation of TFAM contributes to mtDNA stress mediated oxidative stress and neurodegeneration whereas experimental studies demonstrate that TFAM overexpression or enzyme replacement enhances neuronal survival and functions. Therefore, in this review we have highlighted the PGC-1α-TFAM regulatory axis as a central hub linking mitochondrial dysfunction, neuroinflammation and oxidative stress in PD. We further discuss therapeutic opportunities aimed at modulating PGC-1α and TFAM to restore mitochondrial homeostasis, underscoring their potential as promising yet underexplored targets for slowing or halting PD progression.