Life is a self-correcting chemical system that maintains its energy demands by assimilating high-quality energy from the environment into its metabolic circuits. This self-correcting module constantly watches its internal energy levels and makes sure that there is a balance between energy available and energy utilized. One of the key components of this module is an ancient, highly conserved kinase called AMP-activated protein kinase, or AMPK.
The AMPK signaling system plays a pivotal role in maintaining systemic energy homeostasis, through its coordinated actions on the central nervous system and peripheral tissues. Loss of AMPK function results in various metabolic phenotypes in animals and plants. In addition, this loss causes defects in development and growth, through its effect on cell cycle, differentiation and metabolism, cell polarity, and structure in plants, worms, flies and rodents.
AMPK is also an important mediator of the general health benefits of dietary restriction on longevity. It is a multisubstrate, heterotrimeric serine / threonine kinase consisting of one α, one β and one γ subunit. In mammals, there are two α, two β and three γ subunits. The N-terminus of the α subunits contains the catalytic domain as well as a phosphorylation site for upstream kinases. The γ subunits are nucleotide binding regulatory subunits; mutations in γ 2 or γ 3 affect glycogen storage in pigs, or glycogen-storage-associated abnormalities in humans. The β subunits play an obligatory role in complex formation between the α and γ subunits.
AMPK is an intracellular as well as systemic energy-sensing molecule. Falling energy levels cause a shift in the intracellular ATP-to-AMP ratio, resulting in increased AMP binding to the γ subunits with consequent phosphorylation and activation of AMPK α subunits. This step is crucial for AMPK-dependent regulation of several downstream metabolic circuits, including inhibition of energy-consuming biosynthetic processes and activation of energy-producing reactions that generate ATP to restore the intracellular energy balance. In addition, AMPK can also be activated in a ATP to AMP ratio-independent manner. We are only beginning to understand these novel energy-independent physiological functions of AMPK.