The long-term goal is to develop an integrated understanding of the physiological, cellular, biochemical, and molecular mechanisms that enable the mammalian neonate to become metabolically independent. The project focuses on liver. Hepatocytes are somewhat hypoxic and relatively quiescent in utero. Immediately after birth the liver initiates a host of new metabolic activities with large energy demands that can be met only by the coincident development of fully competent aerobic ATP synthesis. Therefore, the rapid engagement of mitochondrial function in liver is an important feature of metabolic adaptation in the newborn. Previous work established that an increase in the adenine nucleotide pool size in the mitochondrial compartment occurs by net uptake from the cytoplasm within a few hours after birth in response to postnatal tissue oxygenation and hormonal signals. The uptake of adenine nucleotides is brought about by exchange with Pi on the mitochondrial ATP-Mg/Pi carrier. The resulting increase in matrix adenine nucleotide concentration is hypothesized to match ATP supply (by activating ATP synthetase) with ATP demand (by stimulating reactions of intermediary metabolism that are localized in the matrix). This coordinate regulation of supply and demand protects cellular ATP during the precarious hypoxic-normoxic transition that occurs at birth. The postnatal increase in matrix adenine nucleotide content is also hypothesized to be an initiating stimulus for mitochondrial biogenesis in the newborn liver. For the next project period there are four aims: (1) To test rigorous hypotheses for the mechanism and regulation of the ATP-Mg/Pi carrier; (2) To determine the physiological signals and intracellular mechanisms that regulate the transport function of the ATP-Mg/Pi carrier in mt hepatocytes; (3) To test the hypothesis that matrix adenine nucleotide content coordinately regulates a) the activity of ATP synthetase and b) gluconeogenesis and ureagenesis through effects on adenine nucleotide dependent matrix reactions, and that this regulation protects cellular ATP during hypoxic episodes; and (4) To investigate how cytochrome oxidase gene expression is regulated in the context of mitochondrial biogenesis in newborn rat liver. These studies are relevant to the medical management of neonates who for various reasons (e.g. respiratory distress, maternal diabetes, respiratory enzyme. deficiencies) are at-risk for failure to develop metabolic and bioenergetic functions of the liver on schedule.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Physical Biochemistry Study Section (PB)
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Tufts University
Schools of Medicine
United States
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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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