Cytochrome aa3 depletion is the cause of the deficient mitochondrial respiration induced by chronic valproate administration.
Liver mitochondria from rats fed 1% (w/w) valproic acid for 75 days displayed an approximate 30% decrease in coupled respiration rates with substrates entering the respiratory chain at complexes I and II. Uncoupling the respiration from proton-pumping, or measuring the respiration without complex IV removed this inhibition. The treatment induced a loss of activity of cytochrome oxidase consistent with a decrease in the mitochondrial content of cytochrome aa3. The inhibition induced by long lasting administration of valproate is apparently located at the site of the proton-pumping activity of complex IV. Furthermore, the capacity of electron transport through complex IV, being far in excess of that required for normal functioning in coupled mitochondria, seems to be controlled by the coupling to proton-pumping in which cytochrome aa3 appears to play a major role.
Laboratory of Physiological Chemistry, Catholic University of Louvain.
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S
Ponchaut
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van Hoof
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K
Veitch
D000818:Animals; D002950:Citrate (si)-Synthase / Q000378:metabolism; D030401:Cytochrome-c Oxidase Deficiency; D003576:Electron Transport Complex IV / Q000096:biosynthesis; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid; D014635:Valproic Acid / Q000008:administration & dosage / Q000633:toxicity*
D005971:Glutamates; D013386:Succinates; D018698:Glutamic Acid; D014635:Valproic Acid; D019802:Succinic Acid; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase