PPARGC1A

Function

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 receptor PPAR-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 (CREB) and nuclear respiratory factors (NRFs). It provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor that regulates muscle fiber type determination. Endurance exercise has been shown to activate the PGC-1α gene in human skeletal muscle. This 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:

1. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), both formed endogenously in the cell as by-products of metabolism but upregulated during times of cellular stress.
2. It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis.
3. 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.
4. cAMP response element-binding (CREB) proteins, activated by an increase in cAMP following external cellular signals.
5. 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.
6. 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:

1. PGC-1α increases Akt (PKB) and Phospho-Akt (Ser 473 and Thr 308) levels in muscle.
2. PGC-1α leads to calcineurin activation.

Akt and calcineurin are both activators of NF kappa B (p65). 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 M2 macrophage polarization 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.

Interactions

PPARGC1A has been shown to interact with:

ERRalpha and PGC-1α are coactivators of both Glucokinase (GK) and SIRT3, binding to an ERRE elements in the GK and SIRT3 promoters.