Coupling of the energetic and purinergic activities of ATP in ischemic and hypoxic disease states

Abstract

Adenosine-5′-triphosphate (ATP) is the single most important molecule in life. It is the universal energy currency of all living things. The energy from ATP is used in the synthesis of RNA/DNA, proteins, and lipids. The energy is used in signal transduction, ion pumping, intracellular and extracellular movement, and heat production. To meet the metabolic demand for ATP, cells utilize oxygen to extract maximal energy from substrates. The dependence on oxygen over the course of evolution allowed cells to grow in size and complexity, but at the same time cells became dependent upon oxygen for cell function and survival. During periods of ischemia or hypoxia, ATP produced by oxidative phosphorylation decreases, cells compensate by increasing glycolytic and substrate level phosphorylation, as well as prioritizing ATP consuming processes. If ischemia or hypoxia continues, extracellular ATP levels increase due to leakage and cell death, and ATP becomes an endogenous ligand that activates purinergic receptors located on cells throughout the body. ATP induces a purinergic response that can vary from cell death to cell proliferation, depending on the concentration of extracellular ATP. The coupling of the energetic and purinergic roles of ATP in ischemia or hypoxia is well illustrated in the leading causes of death in humans in the United States. Intracellular ATP depletion leads to cellular dysfunction and extracellular ATP leads to purinergic mediated responses that attempt to rectify the ischemia or hypoxia issue. Understanding the connections between the energetic and purinergic roles of ATP could be useful in future therapies.