The objective is to understand the cellular and biochemical events that lead to successful metabolic adaptation in early postnatal life. We have shown that perinatal changes in insulin/glucagon andd tissue pO2 regulate the sudden net uptake of adenine nucleotides (ADN) from the liver cytosol into the mitochondria, resulting in a large increase in the matrix ATP+ADP+AMP pool size within a few hours after birth. Mitochondrial ADN uptake occurs via a novel transport mechanism that we propose to characterize in detail. In addition we will investigate the hypothesis that the increased matrix ADN concentration is the initiating signal for an extended program of metabolic development that unfolds subsequently. One immediate effect would be the stimulation (probably by mass action) of key ADN-dependent reactions that are localized in the matrix, e.g.: oxidative phosphorylation, pyruvate carboxylation, short chain fatty acid activation, and citrulline synthesis, that promotes the restoration of energy homeostasis during the critical period of metabolic adjustment immediately after birth. Most interesting is the prospect that early postnatal proliferation of mitochondria is regulated by this mechanism via stimulation of the ADN-dependent matrix reactions required for mitochondrial biogenesis, e.g.: mitochondrial synthesis of cardiolipin, nucleic acids, and protein, and translocation of nuclear-encoded precursor proteins into the mitochondria. Mitochondrial proliferation may in turn be a prerequisite for the optimum development of specialized pathways such as gluconeogenesis, urea synthesis, and fatty acid oxidation, all of which have nuclear-encoded enzymes assigned to the mitrochondria compartment. Mitochondrial proliferation may also be permissive for the onset of postnatal cell division. The temporal sequence of these events, their mechanistic details, and regulatory interrelationships will be studied in newborn rats and rabbits, in vivo and in hepatocytes and isolated mitochondria prepared at various stages of postnatal development. Given that the important physiological signals at parturition are increased pO2 and decreased insulin/glucagon, the effect of respiratory distress and maternal diabetes on normal development will receive special attention.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD016936-07
Application #
3314066
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1983-04-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
Schools of Arts and Sciences
DUNS #
073134835
City
Medford
State
MA
Country
United States
Zip Code
02155
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
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
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
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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