Restoration of hepatic cytochrome c oxidase activity and expression with acetyl-L-carnitine treatment in spf mice with an ornithine transcarbamylase deficiency.
The sparse fur (spf) mutant mouse, with an X-linked ornithine transcarbamylase deficiency, is a model of congenital hyperammonemia in children. Our earlier studies indicated a deficiency of hepatic carnitine, CoA-SH, acetyl CoA, and ATP in spf mice. We have now studied the effects of a 7-day treatment with acetyl-L-carnitine (ALCAR) in the spf/Y mice on the activity and expression of the respiratory chain enzyme cytochrome c oxidase (COX; EC 1.9.3.1). We found decreased hepatic activity and expression of COX in the untreated hyperammonemic spf/Y mice, which was restored upon ALCAR treatment. Because COX is a mitochondrial membrane protein, we also carried out studies to explain the mechanism of ALCAR through its effect on membrane stability. Our results indicate a decrease of the mitochondrial membrane cholesterol/phospholipid molar ratio (CHOL/PL ratio) with the activity and expression of COX in untreated spf/Y mice. While ALCAR treatment normalized the ratios, it also restored the hepatic ATP production to normal. To study further if there was any effect of ALCAR on the mitochondrial matrix urea cycle enzymes, we measured the activity and expression of mutant ornithine transcarbamylase (OTC; EC 2.1.3.3) and normal carbamyl phosphate synthase-I (CPS-I; EC 6.3.4.16) in spf/Y mice. There was no general effect on the specific activities of the matrix enzymes upon ALCAR treatment, although their mRNA levels were enhanced. Our studies point towards the feasibility of an ALCAR treatment in conjunction with other treatment modalities, e.g. sodium benzoate and/or arginine, to improve the availability of cellular ATP and to counteract the effects of hereditary hyperammonemic syndromes in children.
Division of Medical Genetics, Sainte-Justine Hospital and University of Montréal, Québec, Canada.
Y R
YR
Mawal
K V
KV
Rama Rao
I A
IA
Qureshi
D000108:Acetylcarnitine / Q000494:pharmacology*; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000096:biosynthesis / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D004790:Enzyme Induction; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009954:Ornithine Carbamoyltransferase / Q000235:genetics / Q000378:metabolism; D020163:Ornithine Carbamoyltransferase Deficiency Disease; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis
D007527:Isoenzymes; D010743:Phospholipids; D012333:RNA, Messenger; D000108:Acetylcarnitine; D000641:Ammonia; D002784:Cholesterol; D003576:Electron Transport Complex IV; D009954:Ornithine Carbamoyltransferase; D002222:Carbamoyl-Phosphate Synthase (Ammonia)