Adenosine and energy metabolism-relationship to brain bioenergetics

The brain is one of the most metabolically active organs in the body, but because it has a limited capacity to store bioenergetic molecules it requires a continuous supply of oxygen and energy. In order to meet the high metabolic needs of the brain, the blood-brain barrier selectively expresses specific transport systems including glucose transporters and monocarboxylic acid transporters that transport lactate and ketone bodies. As a universal energy source, adenosine triphosphate (ATP) drives biological reactions essential for brain functions, and loss of such cellular energy results in profound abnormalities in brain function. The high-energy phosphate bonds of ATP are rather labile and thus energy inherent in ATP is readily released when ATP is hydrolyzed sequentially to ADP, AMP, and finally adenosine. Although each of these molecules serves different functions and can activate different signaling pathways, our focus here is on adenosine and brain energy metabolism. Under basal conditions, brain levels of adenosine are nearly 10,000-fold lower than ATP. Therefore, unnoticeable and possibly physiologically irrelevant decreases in ATP levels can result in dramatic and physiologically relevant rises in adenosine levels. As brain energy levels drop, adenosine levels rise to adjust brain energy supply and to retaliate against an external stimulus that would otherwise cause excessive ATP breakdown. These actions of adenosine are mediated by adenosine receptors located on target cells including neurons, glial cells, and brain endothelial cells. A critical issue in studying brain bioenergetics is the precise and accurate measurement of levels of ATP and its metabolites including adenosine. Because these molecules can be degraded rapidly, it is challenging to make such measurements. Essential components in the correct assessment of brain energetics should include justifying carefully the methodology used and putting the data in the context of what is already known about brain energy metabolism.