PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha)

PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional co-activator and master regulator of mitochondrial biogenesis and oxidative metabolism that lacks intrinsic DNA-binding activity and instead coordinates transcription by interacting with nuclear receptors (PPARα, ERRα) and other transcription factors (NRF1, NRF1/NRF2 (nuclear respiratory factors — distinct from the antioxidant transcription factor Nrf2/NFE2L2 covered in the nrf2-keap1 entry), TFAM). It is induced by exercise, cold exposure, fasting, and AMPK or SIRT1 activation, and drives the expression of the mitochondrial genome replication machinery and enzymes of fatty acid oxidation and the tricarboxylic acid cycle. PGC-1α expression and activity decline in aged skeletal muscle and heart, contributing to mitochondrial dysfunction and metabolic inflexibility; its overexpression or pharmacological induction has extended healthspan and delayed age-related muscle wasting in several animal models, making it a prominent target in longevity pharmacology.