Mitochondrial O2 use and ATP synthesis: kinetic effects of Ca++ and HPO4(-2) modulated by glucocorticoids.
We have studied the effect of increased Ca++ on rat liver mitochondrial O2 consumption and modulation of the effects of the Ca++ by varying levels of HPO4(-2). Moreover, we have studied the acute in vitro effects of glucocorticoids on this system. Our data indicate that: 1) 200 microM Ca++ produces uncoupled respiration by mitochondria and blocks ATP synthesis: 2) HPO4(-2) increases the velocity and duration of uncoupled O2 consumption induced by Ca++. The HPO4(-2) effect fits Michaelis-Menton kinetics, indicating a specific site for the action of HPO4(-2) with a Km (1/2 saturation constant) of 5 mM; 3) dexamethasone acts acutely (without prefeeding) as an allosteric inhibitor of the HPO4(-2) system; and 5) uptake kinetics done with tritium-labeled dexamethasone into fresh intact human leukocytes demonstrate equilibration into the cell within 60 sec with a very large Vmax of transport at the plasma membrane. Critically ill patients with reduced tissue perfusion have lowered ionized calcium blood levels. This reflects movement of this ion into the cytosol as the plasma membrane Ca++ pump begins to fail. Clinical implications of our study are that: 1) administration of therapeutic Ca++ in hypoperfused patients with low serum Ca++ levels may be contraindicated because this will only increase the Ca++ load on the mitochondria and further depress ATP synthesis; 2) glucocorticoids administered to these patients offer partial protection of the mitochondria from uncoupling and improve ATP synthesis; and 3) effective doses of glucocorticoids are probably near optimum at four to five times the K.
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D010756:Phosphoric Acids / Q000378:metabolism*; D051381:Rats; D012769:Shock / Q000188:drug therapy / Q000378:metabolism
D005938:Glucocorticoids; D010756:Phosphoric Acids; D003907:Dexamethasone; D000255:Adenosine Triphosphate; D002118:Calcium