PGC-1α is thought to be a master integrator of external signals. It is known to be activated by a host of factors, including:
# Reactive oxygen species and reactive nitrogen species, both formed endogenously in the cell as by-products of metabolism but upregulated during times of cellular stress.
#Fasting can also increase gluconeogenic gene expression, including hepatic PGC-1α.
# 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 (CREB) 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 PIP, 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 (PKB) and Phospho-Akt (Ser 473 and Thr 308) levels in muscle.
# 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.