TY - JOUR
T1 - Differential inhibition by hyperammonemia of the electron transport chain enzymes in synaptosomes and nonsynaptic mitochondria in ornithine transcarbamylase-deficient spf-Mice
T2 - Restoration by acetyl-L-carnitine
AU - Qureshi, Karim
AU - Rao, K. V.Rama
AU - Qureshi, Ijaz A.
N1 - Funding Information:
This work was supported by grants from the Medical Research Council of Canada (MRC) and Sigma-Tau, Italy. The technical support of Ms. Diane Leblanc and Ms. Elaine Larouche and the secretarial assistance of Ms. Micheline Patenaude is acknowledged.
PY - 1998
Y1 - 1998
N2 - Sparse-fur (spf) mouse is the ideal animal model to study the neuropathology of congenital ornithine transcarbamylase (OTC) deficiency. Our current hypothesis implies that an ammonia-induced depletion of energy metabolism in the spf mouse, could be due to a reduction in the activities of the enzymes of the electron transport chain and a treatment with acetyl-L- carnitine could normalize this abnormality. We also hypothesized that there might be a differential degree of inhibition in synaptosomal and non-synaptic mitochondria, for the enzymes of the electron transport chain, caused by congenital hyperammonemia. We have therefore measured the activities of NADH- cytochrome C oxidoreductase, succinate cytochrome C oxidoreductase and cytochrome C oxidase in synaptosomes and non-synaptic mitochondria, isolated from spf mice and CD-1 controls with and without acetyl-L-carnitine treatment. Our results indicate a significant reduction (19-34%) in the activities of these complexes in synaptosomes in untreated spf mice, whereas in non-synaptic mitochondria, there was a tendency for the activities to decrease. Acetyl-L-carnitine treatment enhanced these activities (1564%) for all the three enzyme complexes and its effect was more prominent on succinate cytochrome C oxidoreductase activity (64%). These studies point out that: (a) ammonia-induced disturbances in the energy metabolism could be more pronounced in neuronal mitochondria, and (b) the effect of acetyl-L-carnitine on the restoration of cerebral ATP in hyperammonemia could be through an enhancement of the activities of various electron transport chain enzymes.
AB - Sparse-fur (spf) mouse is the ideal animal model to study the neuropathology of congenital ornithine transcarbamylase (OTC) deficiency. Our current hypothesis implies that an ammonia-induced depletion of energy metabolism in the spf mouse, could be due to a reduction in the activities of the enzymes of the electron transport chain and a treatment with acetyl-L- carnitine could normalize this abnormality. We also hypothesized that there might be a differential degree of inhibition in synaptosomal and non-synaptic mitochondria, for the enzymes of the electron transport chain, caused by congenital hyperammonemia. We have therefore measured the activities of NADH- cytochrome C oxidoreductase, succinate cytochrome C oxidoreductase and cytochrome C oxidase in synaptosomes and non-synaptic mitochondria, isolated from spf mice and CD-1 controls with and without acetyl-L-carnitine treatment. Our results indicate a significant reduction (19-34%) in the activities of these complexes in synaptosomes in untreated spf mice, whereas in non-synaptic mitochondria, there was a tendency for the activities to decrease. Acetyl-L-carnitine treatment enhanced these activities (1564%) for all the three enzyme complexes and its effect was more prominent on succinate cytochrome C oxidoreductase activity (64%). These studies point out that: (a) ammonia-induced disturbances in the energy metabolism could be more pronounced in neuronal mitochondria, and (b) the effect of acetyl-L-carnitine on the restoration of cerebral ATP in hyperammonemia could be through an enhancement of the activities of various electron transport chain enzymes.
KW - Acetyl-L-carnitine
KW - Brain
KW - Electron transport chain
KW - Non-synaptic mitochondria
KW - Ornithine transcarbamylase deficiency
KW - Synaptosomes
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U2 - 10.1023/A:1022406911604
DO - 10.1023/A:1022406911604
M3 - Article
C2 - 9572674
AN - SCOPUS:0031979199
SN - 0364-3190
VL - 23
SP - 855
EP - 861
JO - Neurochemical Research
JF - Neurochemical Research
IS - 6
ER -