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.
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