Within minutes or hours of parturition, the maturation of pathways for oxidative phosphorylation, and the onset of significant rates of gluconeogenesis, are important metabolic adjustments required for an adequate neonatal defense against hypoglycemia. Preliminary studies have shown that, in rat and rabbit liver, right after birth, there is a sudden influx of adenine nucleotides from the cytosol into the mitochondria. This is correlated with the development of maximum rates of coupled respiration, and also with the activation of pyruvate carboxylase, the rate-limiting enzyme for gluconeogenesis at birth. These findings suggest a unifying hypothesis to explain how gluconeogenesis, and an adequate rate of ATP synthesis to support it, develop simultaneously within 1-2 hours without new enzyme synthesis: It is proposed that a stimulus associated with parturition triggers the influx of adenine nucleotides into the matrix compartment via a novel transport mechanism that regulates unidirectional movement of ATP and ADP across the inner mitochondrial membrane. As a result, the matrix adenine nucleotide pool size is rapidly increased in magnitude. Any enzymes localized in the matrix, which are also adenine nucleotide-dependent, may thus become suddenly active. Affected reactions include at least those of oxidative phosphorylation (ADP-dependent) and pyruvate carboxylase (ATP-dependent) and this may account for a 3-4 fold increase in gluconeogenesis. Experiments are proposed to test this hypothesis further and to understand the mechanistic details at the cellular-biochemical level. Specific areas to be investigated include: identification of the initiating physiological signals at birth, characterization of the novel ATP, ADP transport mechanism in he mitochondria; the basis for sensitivity of specific matrix reactions to alterations in the ATP+ADP pool size; and the relationship of over-all gluconeogenic rates in isolated hepatocytes to changes in the matrix adenine nucleotide pool size. There are reasons to suspect that neonatal hypoglycemia associated with maternal diabetes, respiratory distress, or prematurity may be caused by a delay in the postnatal influx of adenines into the matrix (which in turn would delay the acture postnatal activation of gluconeogenesis according to the hypothesis proposed;) this idea also will be investigated in animal models as part of this proposal.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Physical Biochemistry Study Section (PB)
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Tufts University
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Joyal, J L; Hagen, T; Aprille, J R (1995) Intramitochondrial protein synthesis is regulated by matrix adenine nucleotide content and requires calcium. Arch Biochem Biophys 319:322-30
Dransfield, D T; Aprille, J R (1994) The influence of hypoxia and anoxia on distribution of adenine nucleotides in isolated hepatocytes. Arch Biochem Biophys 313:156-65
Dougherty, F E; Ernst, S G; Aprille, J R (1994) Familial recurrence of atypical symptoms in an extended pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). J Pediatr 125:758-61
Gross, A W; Aprille, J R; Ernst, S G (1994) Identification of human mitochondrial DNA fragments corresponding to the genes for ATPase, cytochrome C oxidase, and nine tRNAs in a denaturing gradient gel electrophoresis system. Anal Biochem 222:507-10
Yoon, K L; Ernst, S G; Rasmussen, C et al. (1993) Mitochondrial disorder associated with newborn cardiopulmonary arrest. Pediatr Res 33:433-40
Dransfield, D T; Aprille, J R (1993) Regulation of the mitochondrial ATP-Mg/Pi carrier in isolated hepatocytes. Am J Physiol 264:C663-70
Hagen, T; Joyal, J L; Henke, W et al. (1993) Net adenine nucleotide transport in rat kidney mitochondria. Arch Biochem Biophys 303:195-207
Aprille, J R (1993) Mechanism and regulation of the mitochondrial ATP-Mg/P(i) carrier. J Bioenerg Biomembr 25:473-81
Nosek, M T; Aprille, J R (1992) ATP-Mg/Pi carrier activity in rat liver mitochondria. Arch Biochem Biophys 296:691-7
Joyal, J L; Aprille, J R (1992) The ATP-Mg/Pi carrier of rat liver mitochondria catalyzes a divalent electroneutral exchange. J Biol Chem 267:19198-203

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