Effect of pH on metabolism of alpha-ketoglutarate by renal cortical mitochondria

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Abstract
The effect of acid-base perturbations on mitochondrial alpha-ketoglutarate (alpha-KG) metabolism was quantitated by measuring the nitrogen and carbon metabolites of glutamine. alpha-KG metabolized was calculated as the difference between alpha-KG production from glutamine (glutamate deamination plus transamination) and alpha-KG accumulation in the medium. Under all experimental conditions accumulation in the medium of malate plus aspartate was altered similarly to the calculated change in alpha-KG metabolism. Mitochondria from rats with chronic acidosis were compared to pair-fed controls. Chronic acidosis resulted in increased alpha-KG production and its intramitochondrial concentration; the rate of conversion of alpha-KG to succinate was unchanged. When mitochondria from normal animals were incubated at pH 7.0, 7.4, and 7.7, the amount of alpha-KG metabolized was altered, but the magnitude and direction of the response was dependent on the concentration of glutamine (0.5, 1.0, or 5.0 mM). A low pH depressed production but stimulated the subsequent metabolism of alpha-KG, whereas an alkaline pH acted in the opposite fashion. The overall response at a given glutamine concentration depended on which effect predominated. Accordingly, chronic acidosis does not induce adaptive changes, but pH, per se, directly alters intramitochondrial alpha-KG metabolism.