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

Abstract

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 L L-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. ß

Acetyl-L-Carnitine and Nicotinamide for Prevention of Type 1 Diabetes. I-Literature Review which Gave Support to the Treatment. II-Case Report, Evaluation of Five Years Treatment

“…This requires an excess of mitochondrial acetyl-CoA that can be provided by acetyl-L-carnitine. This behavior was similar to hexokinase shunt to increase ADP when ATP synthesis was urgent required [47] Aceyl-L-carnitine be metabolized rapidly when it was injected IV because it was transported to mitochondria directly and acetyl moiety was released into mitochondria by acetyltransferase [38]. This acetyl-CoA was part of acetyl-CoA pool and it participated in the synthesis of glutamate, glutamine, GABA, etc.…”

“…In isolated hepatocytes, the addition of L-carnitine did not increase the ß-oxidation but incremented the availability of mitochondrial acylcarnitines [38] suggesting that L-carnitine in normal concentration was sufficient for high ß-oxidation activity. It has also been observed that peroxisomal acylcarnitines can cross to mitochondria by diffusion without CPT1 activation [42] although the metabolic implication of this transport was not quantified.…”

“…A possible explanation about the protection of apoptosis by acylcarnitines, opposites of apoptosis increments by palmitoyl-carnitine were supported that palmitate, and specifically the palmitoyl-CoA, competing with mitochondrial acetyl-transferases and increments mitochondrial palmitate [37]. Otherwise palmitoil-CoA was the limiting step in ceramide synthesis and its increase could contribute to an increment of ceramide [38].…”

“…The acyl-carnitines activated CPT1 [37] and L-carnitine or acylcarnitines protected the development of apoptosis induced by "dead receptors" like CD95 (also known as Fas or Apo1) while palmitoylcarnitine increased apoptosis [38]. L-carnitine at doses of 200 mg/ Kg/48 h increased "in vivo" the anti-apoptotic hormone IGF-I restoring its levels decreased in diabetes by streptozotocin [39].…”

“…The proposed doses of nicotinamide was demonstrated as without toxicity [70,71] and oral administration of very high doses of L-carnitine only produce diarrhea for osmotic reasons, without toxic signals [38]. However, the deficit of L-carnitine produced cellular damage with neurological manifestation [80] because L-carnitine and its derivatives are physiological regulators of peroxisomes interaction with mitochondria [57].…”