Reduction of phosphate-induced dysfunction in rat heart mitochondria by carnitine.
The direct effects of varying concentrations (5-40 mM) of D,L-carnitine were studied in two populations, subsarcolemmal and interfibrillar, of cardiac mitochondria exposed to inorganic phosphate (Pi). After 5 min preincubation 20 mM Pi significantly depressed oxidative phosphorylation rate and ADP/ATP translocase activity, in both populations. Inclusion of D,L-carnitine during preincubation significantly prevented the Pi-induced depression in oxidative phosphorylation without affecting the ADP/ATP translocate system. The Pi-induced inhibition in mitochondrial oxygen consumption rate was seen with either pyruvate-malate, glutamate-malate or succinate as respiratory substrates and was also observed in uncoupled mitochondria treated with 2,4-dinitrophenol. Mitochondrial swelling and shrinkage studies revealed Pi-induced inner membrane instability, a phenomenon prevented by D,L-carnitine in a dose-dependent manner. The effect of Pi was also observed at a concentration of 5 mM which was also prevented by carnitine. Mepacrine, a phospholipase A2 inhibitor, failed to prevent any of the effects of Pi. The results therefore suggest that Pi can produce a depression in mitochondrial oxidative phosphorylation through a mechanism possibly associated with disturbed inner membrane structure and function but apparently unrelated to phospholipase A2 activation. The salutary actions of carnitine may partly explain its protective effects in the ischemic and reperfused heart, a phenomenon associated with enhanced intracellular Pi accumulation.
Duan
J M
JM
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Karmazyn
M
M
D000818:Animals; D002331:Carnitine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010710:Phosphates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011773:Pyruvates / Q000378:metabolism; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D013386:Succinates / Q000378:metabolism
D010710:Phosphates; D011773:Pyruvates; D013386:Succinates; D000226:Mitochondrial ADP, ATP Translocases; D011796:Quinacrine; D002331:Carnitine