ATP and Brain Function

Abstract

The importance of A TP as the main source of chemical energy in living matter and its involve ment in cellular processes has long been recog nized. The primary mechanism whereby higher or ganisms, including humans, generate ATP is through mitochondrial oxidative phosphorylation. For the majority of organs, the main metabolic fuel is glucose, which in the presence of oxygen under goes complete combustion to CO 2 and H 2 0:The free energy (.:lG) liberated in this exergonic re action is partially trapped as ATP in two consecu tive processes: glycolysis (cytosol) and oxidative phosphorylation (mitochondria). The first produces 2 mol of ATP per mol of glucose, and the second 36 mol of ATP per mol of glucose. In the latter case, 6 mol of ATP are contributed from the oxidation of 2 mol of NADH generated in the cytosol during gly colysis and transferred into the mitochondria indi rectly through various "shuttle" systems. (In the a-glycerophosphate shuttle, the yield of ATP per NADH is reduced from 3 to 2 because the relevant mitochondrial dehydrogenase is a flavoprotein linked enzyme). Thus, oxidative phosphorylation yields 17-18 times as much useful energy in the form of ATP as can be obtained from the same amount of glucose by glycolysis alone. It is there fore not surprising that limitation of O 2 supply pro duces very damaging effects on cellular function. The brain is one of the organs that is particularly sensitive to lack of oxygen and in humans at rest is responsible for 20% of total O 2 consumption al though it accounts for only 2% of the body weight. in the function of the CNS? It will become evident from our discussion that only partial an swers to these questions are currently available. However, the search for these solutions involves some of the most exciting areas of contemporary neurochemistry. CONCENTRA nONS OF HIGH ENERGY PHOSPHATE COMPOUNDS IN MAMMALIAN BRAINBrain, like all other organs in the body, contains phosphorylated nucleotides that yield energy upon hydrolysis of their phosphate bond(s); the most im portant of these is the adenine nucleotide ATP. In addition, the CNS, in common with other excitable tissues, possesses another high energy reservoir, the creatine phosphate/creatine (PCr/Cr) system,

Focal and Perifocal Changes in Tissue Energy State during Middle Cerebral Artery Occlusion in Normo- and Hyperglycemic Rats

“…The former must determine the balance between exergonic and endergonic reactions and thereby cell damage, while the latter is a major determinant of extra-and intracellular pH. In discussing these important modulators of cell damage, we make the tacit as sumption that changes in the chemically measured ADP and AMP concentrations reflect correspond ing changes in the free ADP and AMP concentra tions (see Erecinska and Silver, 1989); also that Values are means ± SD. MCA, middle cerebral artery; CX, neocortex; PCr, phosphocreatine; Cr, creatine; EC, adenylate energy charge.…”

The Oxygen Paradox of Neurovascular Coupling

“…of arterial blood 9,000 nmoL/mL Glucose conc. of arterial blood 5,000-6,000 nmoL/mL 53 Oxygen extraction fraction 30%-55% 3,5,6,27,75,93 Glucose extraction fraction 8%-15% ATP concentration of brain tissue 1,000-3,000 nmoL/mL 124,137,138 Total ADP concentration of brain tissue 300 nmoL/mL 124,138 Free ADP concentration of brain tissue 30-35 nmoL/mL [121][122][123] PCr concentration of brain tissue 4,000-5,000 nmoL/mL 123,124,138 Diffusion constant for O2 in brain 78 Assuming mitochondrial oxygen tension close to zero (meaning so low that any further reduction would limit oxidative metabolism), the driving force for oxygen delivery, the gradient between the capillary and mitochondria, can only be increased by an increase in capillary oxygen tension, which in turn requires a decrease of the oxygen extraction fraction. Later, the observation of constant CMRO 2 during pharmacological reductions of CBF led to a modification of the model by incorporating potential changes of cytochrome c oxidase affinity to oxygen during increases in neuronal activity.…”

Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research

“…Acting as a reservoir for the generation of ATP, the high-energy compound PCr is synthesized from Cr and ATP by the catalyzing agent creatine kinase (CPK) (Figure 2). 69 During periods of acute neuronal activity, as molecules of ATP are utilized by Na þ /K þ ATPase, PCr is rapidly broken down in order to maintain the overall concentration of ATP. 69,70 Although short-term decreases in PCr concentration thus indicate immediate cell activity, as can be observed in episodes of photic stimulation, 71 longterm abnormalities in PCr concentration generally reflect much larger alterations in cellular metabolism, and in particular an insufficient supply of the ATP needed for normal cellular function.…”