All cellular metabolism, i.e. anabolism, catabolism and transport, is intimately coupled to the cellular energy level as expressed in the [ATP]/[ADP][Pi]. Mitochondrial oxidative phosphorylation is primarily responsible for maintaining the energy level and it thereby strongly influences all other metabolism. Our objective is to gain an understanding of the regulation of cellular metabolism and in this project we will concentrate on the role of oxygen and intracellular pH in metabolic homeostasis. In order to approach this general question we will: 1. Examine the oxygen dependence of mitochondrial oxidative phosphorylation in vivo as it is expressed in the cytoplasmic [ATP]/[ADP][Pi] and [NAD]/[NADH], the mitochondrial [NAD]/[NADH] and in the behavior of the energy requiring metabolic reactions such as gluconeogenesis, urea synthesis and protein synthesis. 2. Examine the proposal that mitochondrial oxidative phosphorylation is the primary oxygen sensor for regulation of tissue oxygen tension through control of local vascular resistance. 3. Measure the oxygen dependence of prostaglandin synthesis by cultured endothelial cells. 4. Establish the relationship of intracellular to extracellular pH in suspensions of isolated hepatocytes and then determine the pH dependence of gluconeogenesis, urea synthesis, respiration, [ATP]/[ADP][Pi], etc. The dependence of regulatory hormone function (norepinephyrine, glucagon) on intra and extracellular pH will also be measured. 5. Measure in vitro dependence of the apparent Km for oxygen on pH, [ATP]/[ADP][Pi] and reduction of cytochrome c using suspensions of isolated mitochondria.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM021524-11
Application #
3270560
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1974-11-01
Project End
1989-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
11
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wilson, D F (1994) Factors affecting the rate and energetics of mitochondrial oxidative phosphorylation. Med Sci Sports Exerc 26:37-43
Greenbaum, N L; Wilson, D F (1991) Role of intramitochondrial pH in the energetics and regulation of mitochondrial oxidative phosphorylation. Biochim Biophys Acta 1058:113-20
Wilson, D F (1990) Contribution of diffusion to the oxygen dependence of energy metabolism in cells. Experientia 46:1160-2
Rumsey, W L; Schlosser, C; Nuutinen, E M et al. (1990) Cellular energetics and the oxygen dependence of respiration in cardiac myocytes isolated from adult rat. J Biol Chem 265:15392-402
Robiolio, M; Rumsey, W L; Wilson, D F (1989) Oxygen diffusion and mitochondrial respiration in neuroblastoma cells. Am J Physiol 256:C1207-13
Wilson, D F; Rumsey, W L; Vanderkooi, J M (1989) Oxygen distribution in isolated perfused liver observed by phosphorescence imaging. Adv Exp Med Biol 248:109-15
Griffin-Green, E A; Zaleska, M M; Erecinska, M (1988) Adriamycin-induced lipid peroxidation in mitochondria and microsomes. Biochem Pharmacol 37:3071-7
Rumsey, W L; Kilpatrick, L; Wilson, D F et al. (1988) Myocardial metabolism and coronary flow: effects of endotoxemia. Am J Physiol 255:H1295-304
Wilson, D F; Rumsey, W L; Green, T J et al. (1988) The oxygen dependence of mitochondrial oxidative phosphorylation measured by a new optical method for measuring oxygen concentration. J Biol Chem 263:2712-8
Wilson, D F; Rumsey, W L (1988) Factors modulating the oxygen dependence of mitochondrial oxidative phosphorylation. Adv Exp Med Biol 222:121-31

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