Abstract

There are 3 major objectives of this project, centered about the biochemical basis of respiratory energy transduction by the mitochondria of animal tissues. The first is the determination of the number, site, and mechanism by which H+ and electric charges are translocated across the inner mitochondrial membrane as each pair of electrons passes from organic substrate to O2 via the electron transport chain. Special attention will be placed on the vectorial processes associated with the cytochrome oxidase reaction and how it responds to intracellular concentrations of ATP, ADP, and phosphate, as well as 02. The second objective is to determine the mechanism and modes of regulation of inward and outward transport of essential metabolites by respiring mitochondria, particularly at intracelluar conditions. Special attention will be given to the respiration-dependent transport of Ca++ at the very low Ca++ concentrations in intact cells, as well as its biological regulation. Also to be examined is the transport of CO2 and bicarbonate and its effect on mitochondrial respiration and bioenergetics. Our third objective is to determine the mode of biosynthesis of 3-phosphocitrate, a mitochondrial inhibitor of calcium phosphate crystalization, which we have found inhibits kidney calcification in vivo. Its concentration and mode of action in cells and mitochondria will be investigated.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM005919-27
Application #
3267889
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1979-03-01
Project End
1989-02-28
Budget Start
1985-03-01
Budget End
1986-02-28
Support Year
27
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Ferreira, J; Reynafarje, B; Costa, L E et al. (1988) Proton stoichiometry of electron transport in rodent tumor mitoplasts. Cancer Res 48:628-34
Beavis, A D (1987) Upper and lower limits of the charge translocation stoichiometry of cytochrome c oxidase. J Biol Chem 262:6174-81
Beavis, A D (1987) Upper and lower limits of the charge translocation stoichiometry of mitochondrial electron transport. J Biol Chem 262:6165-73
Reynafarje, B; Costa, L E; Lehninger, A L (1986) Upper and lower limits of the proton stoichiometry of cytochrome c oxidation in rat liver mitoplasts. J Biol Chem 261:8254-62
Balboni, E; Lehninger, A L (1986) Entry and exit pathways of CO2 in rat liver mitochondria respiring in a bicarbonate buffer system. J Biol Chem 261:3563-70
Turrens, J F; Bickar, D; Lehninger, A L (1986) Inhibitors of the mitochondrial cytochrome b-c1 complex inhibit the cyanide-insensitive respiration of Trypanosoma brucei. Mol Biochem Parasitol 19:259-64
Bickar, D; Turrens, J F; Lehninger, A L (1986) The mechanism by which oxygen and cytochrome c increase the rate of electron transfer from cytochrome a to cytochrome a3 of cytochrome c oxidase. J Biol Chem 261:14461-6
Beavis, A D; Lehninger, A L (1986) The upper and lower limits of the mechanistic stoichiometry of mitochondrial oxidative phosphorylation. Stoichiometry of oxidative phosphorylation. Eur J Biochem 158:315-22
Beavis, A D; Lehninger, A L (1986) Determination of the upper and lower limits of the mechanistic stoichiometry of incompletely coupled fluxes. Stoichiometry of incompletely coupled reactions. Eur J Biochem 158:307-14
Reynafarje, B; Costa, L E; Lehninger, A L (1985) O2 solubility in aqueous media determined by a kinetic method. Anal Biochem 145:406-18

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