Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine.
L-Carnitine facilitates the transport of fatty acids into the mitochondrial matrix where they are used for energy production. Recent studies have shown that L-carnitine is capable of protecting the heart against ischemia/reperfusion injury and has beneficial effects against Alzheimer's disease and AIDS. The mechanism of action, however, is not yet understood. In the present study, we found that in Jurkat cells, L-carnitine inhibited apoptosis induced by Fas ligation. In addition, 5 mM carnitine potently inhibited the activity of recombinant caspases 3, 7 and 8, whereas its long-chain fatty acid derivative palmitoylcarnitine stimulated the activity of all the caspases. Palmitoylcarnitine reversed the inhibition mediated by carnitine. Levels of carnitine and palmitoyl-CoA decreased significantly during Fas-mediated apoptosis, while palmitoylcarnitine formation increased. These alterations may be due to inactivation of beta-oxidation or to an increase in the activity of the enzyme that converts carnitine to palmitoylcarnitine, carnitine palmitoyltransferase I (CPT I). In support of the latter possibility, fibroblasts deficient in CPT I activity were relatively resistant to staurosporine-induced apoptosis. These observations suggest that caspase activity may be regulated in part by the balance of carnitine and palmitoylcarnitine.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
M C
MC
Mutomba
H
H
Yuan
M
M
Konyavko
S
S
Adachi
C B
CB
Yokoyama
V
V
Esser
J D
JD
McGarry
B M
BM
Babior
R A
RA
Gottlieb
D000215:Acylation; D017209:Apoptosis / Q000187:drug effects*; D002331:Carnitine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts; D006801:Humans; D019169:Jurkat Cells; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D010172:Palmitoylcarnitine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D019311:Staurosporine / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology*
D061945:Caspase Inhibitors; D019014:fas Receptor; D010171:Palmitoyl Coenzyme A; D010172:Palmitoylcarnitine; D002334:Carnitine O-Palmitoyltransferase; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D019311:Staurosporine; D002331:Carnitine