{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T17:34:33Z","timestamp":1760204073996},"reference-count":0,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2004,7,12]],"date-time":"2004-07-12T00:00:00Z","timestamp":1089590400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2005,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Mitochondrial \u03b2\u2010ketothiolase and 2\u2010methyl\u20103\u2010hydroxybutyryl\u2010CoA dehydrogenase (MHBD) deficiencies are inherited neurometabolic disorders affecting isoleucine catabolism. Biochemically, \u03b2\u2010ketothiolase deficiency is characterized by intermittent ketoacidosis and urinary excretion of 2\u2010methyl\u2010acetoacetate (MAA), 2\u2010methyl\u20103\u2010hydroxybutyrate (MHB) and tiglylglycine (TG), whereas in MHBD deficiency only MHB and tiglylglycine accumulate. Lactic acid accumulation and excretion are also observed in these patients, being more pronounced in MHBD\u2010deficient individuals, particularly during acute episodes of decompensation. Patients affected by MHBD deficiency usually manifest severe mental retardation and convulsions, whereas \u03b2\u2010ketothiolase\u2010deficient patients present encephalopathic crises characterized by metabolic acidosis, vomiting and coma. Considering that the pathophysiological mechanisms responsible for the neurological alterations of these disorders are unknown and that lactic acidosis suggests an impairment of energy production, the objective of the present work was to investigate the <jats:italic>in vitro<\/jats:italic> effect of MAA and MHB, at concentrations varying from 0.01 to 1.0\u2009mmol\/L, on several parameters of energy metabolism in cerebral cortex from young rats. We observed that MAA markedly inhibited CO<jats:sub>2<\/jats:sub> production from glucose, acetate and citrate at concentrations as low as 0.01\u2009mmol\/L. In addition, the activities of the respiratory chain complex II and succinate dehydrogenase were mildly inhibited by MAA. MHB, at 0.01\u2009mmol\/L and higher concentrations, strongly inhibited CO<jats:sub>2<\/jats:sub> production from all tested substrates, as well as the respiratory chain complex IV activity. The other activities of the respiratory chain were not affected by these metabolites. The data indicate a marked blockage in the Krebs cycle and a mild inhibition of the respiratory chain caused by MAA and MHB. Furthermore, MHB inhibited total and mitochondrial creatine kinase activities, which was prevented by the use of the nitric\u2010oxide synthase inhibitor L\u2010NAME and glutathione (GSH). These data indicate that the effect of MHB on creatine kinase was probably mediated by oxidation or other modification of essential thiol groups of the enzyme by nitric oxide and other by\u2010products derived from this organic acid. In contrast, MAA did not affect creatine kinase activity. Taken together, these observations indicate that aerobic energy metabolism is inhibited by MAA and to a greater extent by MHB, a fact that may be related to lactic acidaemia occurring in patients affected by MHBD and \u03b2\u2010ketothiolase deficiencies. If the <jats:italic>in vitro<\/jats:italic> effects detected in the present study also occur <jats:italic>in vivo<\/jats:italic>, it is tempting to speculate that they may contribute, at least in part, to the neurological dysfunction found in these disorders.<\/jats:p>","DOI":"10.1007\/s10545-005-0501-3","type":"journal-article","created":{"date-parts":[[2005,5,17]],"date-time":"2005-05-17T12:50:32Z","timestamp":1116334232000},"page":"501-515","source":"Crossref","is-referenced-by-count":18,"title":["Inhibition of energy metabolism by 2\u2010methylacetoacetate and 2\u2010methyl\u20103\u2010hydroxybutyrate in cerebral cortex of developing rats"],"prefix":"10.1002","volume":"28","author":[{"given":"R. B.","family":"Rosa","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. F.","family":"Schuck","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. R. de","family":"Assis","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Latini","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"},{"name":"Servi\u00e7o de Gen\u00e9tica M\u00e9dica Hospital de Cl\u00ednicas de Porto Alegre  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K. B.","family":"Dalcin","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. A. J.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. da C.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. C.","family":"Maria","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G.","family":"Leipnitz","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. L. S.","family":"Perry","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. S. Dutra","family":"Filho","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. T. S.","family":"Wyse","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. M. D.","family":"Wannmacher","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Wajner","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Ci\u00eancias B\u00e1sicas da Sa\u00fade Universidade Federal do Rio Grande do Sul  Porto Alegre RS"},{"name":"Servi\u00e7o de Gen\u00e9tica M\u00e9dica Hospital de Cl\u00ednicas de Porto Alegre  Porto Alegre RS"},{"name":"Universidade Luterana do Brasil  Canoas RS Brazil"},{"name":"Departamento de Bioqu'mica, ICBS Universidade Federal do Rio Grande do Sul  Rua Ramiro Barcelos, 2600\u2013Anexo, CEP 90035\u2010003 Porto Alegre RS Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2004,7,12]]},"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1007\/s10545-005-0501-3","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1007\/s10545-005-0501-3","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T00:22:10Z","timestamp":1694737330000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1007\/s10545-005-0501-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,7,12]]},"references-count":0,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2005,6]]}},"alternative-id":["10.1007\/s10545-005-0501-3"],"URL":"https:\/\/doi.org\/10.1007\/s10545-005-0501-3","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,7,12]]}}}