Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine

• Published in: FEBS letters 2000-07, Vol.478 (1), p.19-25
• Main Authors: Mutomba, Martha C., Yuan, Hua, Konyavko, Mary, Adachi, Souichi, Yokoyama, Christopher B., Esser, Victoria, McGarry, J.Denis, Babior, Bernard M., Gottlieb, Roberta A.
• Format: Article
• Language: English
• Subjects: Acylation; Apoptosis; Apoptosis - drug effects; Carnitine - analogs & derivatives; Carnitine - antagonists & inhibitors; Carnitine - metabolism; Carnitine - pharmacology; Carnitine O-Palmitoyltransferase - deficiency; Carnitine O-Palmitoyltransferase - genetics; Carnitine O-Palmitoyltransferase - metabolism; Carnitine palmitoyltransferase I; Caspase; Caspase 3; Caspase 7; Caspase 8; Caspase 9; Caspase Inhibitors; Caspase, cysteine aspartic acid specific protease; Caspases - metabolism; Cell Line; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; CPT, carnitine palmitoyltransferase; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; fas Receptor - physiology; Fibroblasts; Humans; Jurkat Cells; L-Carnitine; Palmitoyl Coenzyme A - metabolism; Palmitoylcarnitine; Palmitoylcarnitine - antagonists & inhibitors; Palmitoylcarnitine - metabolism; Palmitoylcarnitine - pharmacology; PARP, recombinant poly(ADP-ribose) polymerase; SDS–PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; Staurosporine - pharmacology
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(00)01817-2

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 β-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.