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.
Mutomba
M C
MC
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Yuan
H
H
Konyavko
M
M
Adachi
S
S
Yokoyama
C B
CB
Esser
V
V
McGarry
J D
JD
Babior
B M
BM
Gottlieb
R A
RA
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