The inhibition of mitochondrial dicarboxylate transport by inorganic phosphate, some phosphate esters and some phosphonate compounds.
1. P(i) competitively inhibited succinate oxidation by intact uncoupled mitochondria in the presence of sufficient N-ethylmaleimide to block the phosphate carrier, with a K(i) of 2.5mm. 2. Of a large number of phosphate esters and phosphonate compounds, phenyl phosphate and phenylphosphonate were found to inhibit competitively uncoupled succinate oxidation by intact but not broken mitochondria. By comparison, benzoate was a relatively weak competitive inhibitor of succinate oxidation by intact mitochondria but a relatively potent inhibitor of succinate dehydrogenase. 3. Phenyl phosphate and phenylphosphonate were non-penetrant, and inhibited P(i)-dependent swelling of mitochondria suspended in isosmolar ammonium malate in a manner non-competitive with P(i). The inhibitors did not affect mitochondrial swelling when tested with P(i) alone. 4. It is concluded that: (i) phenyl phosphate and phenylphosphonate behaved as non-penetrant analogues of P(i), since their inhibitory properties were in strict contrast with those of benzoate; (ii) phenyl phosphate and phenylphosphonate interacted with the dicarboxylate carrier but not with the phosphate carrier; (iii) P(i) was effective as a competitive inhibitor of succinate oxidation because of its being either an alternative substrate for the dicarboxylate carrier or competitive with succinate for the intramitochondrial cations as proposed by Harris & Manger (1968).
D000249:Adenosine Monophosphate / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D001692:Biological Transport; D004952:Esters / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D005636:Fructosephosphates / Q000494:pharmacology; D005958:Glucosephosphates / Q000494:pharmacology; D005994:Glycerophosphates / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D009596:Nitrophenols / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010710:Phosphates / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000494:pharmacology*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors; D013386:Succinates / Q000378:metabolism*
D001565:Benzoates; D004952:Esters; D005636:Fructosephosphates; D005958:Glucosephosphates; D005994:Glycerophosphates; D009596:Nitrophenols; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D010710:Phosphates; D010756:Phosphoric Acids; D013386:Succinates; D000249:Adenosine Monophosphate; D013385:Succinate Dehydrogenase; D005033:Ethylmaleimide