PGC-1α is a transcriptional coactivator that regulates the genes involved in energy metabolism. It is the master regulator of mitochondrial biogenesis. This protein interacts with the nuclear receptorPPAR-γ, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activities of, cAMP response element-binding protein and nuclear respiratory factors . It provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor causing slow-twitch rather than fast-twitch muscle fiber types. Endurance exercise has been shown to activate the PGC-1α gene in human skeletal muscle. Exercise-induced PGC-1α in skeletal muscle increases autophagy and unfolded protein response. PGC-1α protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.
Regulation
PGC-1α is thought to be a master integrator of external signals. It is known to be activated by a host of factors, including:
It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis.
It is induced by endurance exercise and recent research has shown that PGC-1α determines lactate metabolism, thus preventing high lactate levels in endurance athletes and making lactate as an energy source more efficient.
cAMP response element-binding proteins, activated by an increase in cAMP following external cellular signals.
Protein kinase B / Akt is thought to downregulate PGC-1α, but upregulate its downstream effectors, NRF1 and NRF2. Akt itself is activated by PIP3, often upregulated by PI3K after G-protein signals. The Akt family is also known to activate pro-survival signals as well as metabolic activation.
SIRT1 binds and activates PGC-1α through deacetylation inducing gluconeogenesis without affecting mitochondrial biogenesis.
PGC-1α has been shown to exert positive feedback circuits on some of its upstream regulators:
PGC-1α increases Akt and Phospho-Akt levels in muscle.
Akt and calcineurin are both activators of NF kappa B. Through their activation PGC-1α seems to activate NF kappa B. Increased activity of NF kappa B in muscle has recently been demonstrated following induction of PGC-1α. The finding seems to be controversial. Other groups found that PGC-1s inhibit NF kappa B activity. The effect was demonstrated for PGC-1 alpha and beta. PGC-1α has also been shown to drive NAD biosynthesis to play a large role in renal protection in Acute Kidney Injury.
Clinical significance
Recently PPARGC1A has been implicated as a potential therapy for Parkinson's disease conferring protective effects on mitochondrial metabolism. Moreover, brain-specific isoforms of PGC-1alpha have recently been identified which are likely to play a role in other neurodegenerative disorders such as Huntington's disease and Amyotrophic lateral sclerosis. Massage therapy appears to increase the amount of PGC-1α which leads to the production of new mitochondria. PGC-1α and beta has furthermore been implicated in polarization to anti-inflammatory M2 macrophages by interaction with PPARγ with upstream activation of STAT6. An independent study confirmed the effect of PGC-1 on polarisation of macrophages towards M2 via STAT6/PPAR gamma and furthermore demonstrated that PGC-1 inhibits proinflammatory cytokine production. PGC-1α has been recently proposed to be responsible for β-aminoisobutyric acid secretion by exercising muscles. The effect of β-aminoisobutyric acid in white fat includes the activation of thermogenic genes that prompt the browning of white adipose tissue and the consequent increase of background metabolism. Hence, the β-aminoisobutyric acid could act as a messenger molecule of PGC-1α and explain the effects of PGC-1α increase in other tissues such as white fat.
