Phosphorus magnetic resonance spectroscopy studies of the role of mitochondria in the disease process.

The incisive detection of bioenergetic insufficiency in an organ of known workload by P MRS is noninvasive and nondestructive, and in some cases the portion of the organ involved can be determined, particularly if both PCr and ATP are depleted. The fractional loss of ATP and hence the relative volumes of viable and "metabolically dead" tissue are thereby evaluated. In addition, the value of P MRS in following a therapy complements its value in diagnosis as this has been demonstrated in cases followed over 6 months to three years. The fact that deficiencies of the enzymes and substrates of oxidative metabolism can be detected by P MRS affords a global overview of energy metabolism that can be a key to rapid diagnosis. The distinction of the enzyme and/or substrate deficiency, while not directly indicated by steady state P MRS, can be identified by use of the "Crossover Theorem" and its impact upon blood and tissue levels of substrates (including oxygen). In the case of neonatal systemic hypoxia, there is no doubt about which of the equations applies, and similarly in metabolic disease, a glutaric acid urea is a direct consequence of the crossover response of metabolism and signifies that an enzyme deficiency may be involved. Furthermore, the clinical danger of a high Pi/PCr value is clarified by our observations, both from the animal models and from the theory, the high clues; i.e. 2 and over, suggest work stresses near the capability of oxidative metabolism and imminent failure of the negative feedback afforded by metabolic regulation, particularly ADP control of oxidative metabolism. This control is lost because of the fall of phosphocreatine to the point where creatine kinase is no longer in equilibrium, leading to the loss of ATP and its conversion to large amounts of ADP and its breakdown products. ATP then stimulates glycolysis and results in a massive lactic acidosis. At the same time, the low thermodynamic capability of glycolytic metabolism is unable to prevent irreversible ion disequilibration, water movements, edema, and eventually rupture of the cell membrane. The pathway of resynthesis of ATP is then tortuous, particularly as AMP is deaminated and adenosine is converted eventually to hypoxanthine. Thus, NMR reports that metabolic control is operating in the region where homeostasis of biochemical parameters is feasible. It further reports regions where the metabolic control is susceptible to failure and most aggressive clinical care is required.