Role of mitochondrial glutaminase in rat renal glutamine metabolism

During normal acid-base balance, the kidney extracts very little of the pla sma glutamine. However, during metabolic acidosis, as much as one third of the plasma glutamine is extracted and metabolized in a single pass through this organ. The substantial increase in renal utilization occurs solely wit hin the proximal convoluted tubule and is sustained by compensating adaptat ions in the intraorgan metabolism of glutamine. The primary pathway for ren al glutamine metabolism involves its transport into mitochondria and its de amidation and deamination by glutaminase (GA) and glutamate dehydrogenase ( GDH), respectively, The resulting ammonium ions are excreted predominantly in the urine where they function as expendable cations to facilitate the ex cretion of acids. The resulting alpha -ketoglutarate is further metabolized to phosphoeno/pyruvate and subsequently to glucose or CO2. The intermediat e steps yield two bicarbonate ions that are selectively transported into th e venous blood to partially compensate the metabolic acidosis. In rat kidne y, this adaptation is sustained in part by the cell-specific induction of t he glutaminase that results primarily from stabilization of the GA mRNA. Th e 3 ' -nontranslated region of the GA mRNA contains a direct repeat of an 8 -base AU-sequence that functions as a pH-response element. This sequence ex hibits a high affinity and specificity for zeta (z)-crystallin. The same pr otein binds to two separate, but homologous, 8-base AU-sequences within the 3 ' -nontranslated region of the GDH mRNA. The apparent binding activity o f z-crystallin is increased significantly during onset of metabolic acidosi s. Thus, increased binding of z-crystallin may initiate the pH-responsive s tabilization of the two mRNAs.