Duramycin effects on the structure and function of heart mitochondria. II. Energy conversion reactions.
The polypeptide antibiotic duramycin has been reported to interact selectively with phosphatidylethanolamine (PE) and monogalactosyldiacylglycerol (Navarro et al., 1985, Biochemistry 24, 4645-4650). PE is a major component of mitochondrial membranes. Duramycin was used to probe the role of PE in mitochondrial energy conversion reactions with the following results: (i) Duramycin uncoupled mitochondrial respiration, decreasing the respiratory control ratio to 1 at 5 microM. At concentrations of duramycin in excess of 10 microM, ADP addition inhibited electron transport. (ii) Duramycin inhibited oxidative phosphorylation (C50 less than 2 microM). (iii) Duramycin stimulated mitochondrial ATP hydrolysis modestly. The antibiotic was 7- to 16-fold less effective in this regard than concentrations of carbonylcyanide p-trifluoromethoxyphenylhydrazone (F-CCP) which produced comparable uncoupling. (iv) Duramycin inhibited uncoupled ATPase activity (C50 = 8 microM). Inhibition of the ATPase activity of intact mitochondria was blocked by 1 mM MgCl2 and 5 mM CaCl2; inhibition persisted in sub-mitochondrial particles assayed in the presence of 3 mM MgCl2. The effects on mitochondrial function of free fatty acids (FFA) and duramycin are similar in many respects. It is suggested that duramycin, like FFA, uncouples via a nonclassical mechanism, possibly by disrupting intramembrane H+ transfer between redox and ATPase complexes. In addition, interaction of duramycin, either direct or indirect, with the F0 moiety of the mitochondrial ATPase and with one or more components of the respiratory electron transport chain is proposed.
Sokolove
P M
PM
Department of Pharmacology & Experimental Therapeutics, University of Maryland Medical School, Baltimore 21201.
Kester
M B
MB
Westphal
P A
PA
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001430:Bacteriocins; D002118:Calcium / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D003574:Cytochrome c Group; D010455:Peptides; C040522:duramycin; D000251:Adenosine Triphosphatases; D008274:Magnesium; D002118:Calcium