218 ACUTE POSTNATAL REGULATION OF PYRUVATE CARBOXYLASE ACTIVITY BY COMPARTMENTATION OF ADENINE NUCLEOTIDES

Abstract

In the term rat liver, crossover studies reveal that pyruvate carboxylase (PC) is rate-limiting for gluconeogenesis. Within 1 hr of birth, the rate of gluconeogenesis increases 4 fold, even though there is no net synthesis of PC. (Biochem. J. 124:265(1971) This suggests that PC is inactive at birth, and becomes active within a short time. PC is localized in the mitochondrial compartment, and requires ATP as a substrate. Since the total adenine nucleotide content (ATP+ADP+AMP) of the matrix increases right after birth (Archiv. Biochem. Biophys. 201:564(1980), we considered whether the resulting increase in matrix ATP concentration might cause an increase in PC activity. We found that PC activity measured in intact isolated mitochondria increased ∼ 3 fold within a few hours of birth, in parallel to a ∼ 3 fold increase in the total matrix adenine nucleotide content. The increase in PC activity could be brought about in vitro by incubating isolated newborn mitochondria with exogenous ATP under conditions shown to promote the net accumulation of adenine nucleotides. Conversely, adult mitochondria specifically depleted of matrix adenine nucleotides had proportionately lower PC activity. We concluded that acute regulation of PC can occur by compartmentation of adenine nucleotides. This mechanism probably provides for the rapid 4-5 fold increase in gluconeogenesis which occurs within 1-2 hrs of birth, without the need for new enzyme synthesis. [Supported by NIH HD11697 and NS 14936.]