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Patients commonly present severe cardiomyopathy for which the pathogenesis is still poorly established. We investigated the effects of 3<jats:styled-content style=\"fixed-case\">HTA<\/jats:styled-content> and 3<jats:styled-content style=\"fixed-case\">HPA<\/jats:styled-content>, the major metabolites accumulating in these disorders, on important parameters of mitochondrial homeostasis in Ca<jats:sup>2+<\/jats:sup>\u2010loaded heart mitochondria. 3<jats:styled-content style=\"fixed-case\">HTA<\/jats:styled-content> and 3<jats:styled-content style=\"fixed-case\">HPA<\/jats:styled-content> significantly decreased mitochondrial membrane potential, the matrix <jats:styled-content style=\"fixed-case\">NAD<\/jats:styled-content>(P)H pool and Ca<jats:sup>2+<\/jats:sup> retention capacity, and also induced mitochondrial swelling. These fatty acids also provoked a marked decrease of <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content> production reflecting severe energy dysfunction. Furthermore, 3<jats:styled-content style=\"fixed-case\">HTA<\/jats:styled-content>\u2010induced mitochondrial alterations were completely prevented by the classical mitochondrial permeability transition (mPT) inhibitors cyclosporin A and <jats:styled-content style=\"fixed-case\">ADP<\/jats:styled-content>, as well as by ruthenium red, a Ca<jats:sup>2+<\/jats:sup> uptake blocker, indicating that <jats:styled-content style=\"fixed-case\">LCHFA<\/jats:styled-content>s induced Ca<jats:sup>2+<\/jats:sup>\u2010dependent mPT pore opening. Milder effects only achieved at higher doses of <jats:styled-content style=\"fixed-case\">LCHFA<\/jats:styled-content>s were observed in brain mitochondria, implying a higher vulnerability of heart to these fatty acids. By contrast, 3<jats:styled-content style=\"fixed-case\">HTA<\/jats:styled-content> and docosanoic acids did not change mitochondrial homeostasis, indicating selective effects for monocarboxylic <jats:styled-content style=\"fixed-case\">LCHFA<\/jats:styled-content>s. The present data indicate that the major <jats:styled-content style=\"fixed-case\">LCHFA<\/jats:styled-content>s accumulating in mitochondrial trifunctional protein and long\u2010chain 3\u2010hydroxyacyl\u2010CoA dehydrogenase deficiencies induce mPT pore opening, compromising Ca<jats:sup>2+<\/jats:sup> homeostasis and oxidative phosphorylation more intensely in the heart. It is proposed that these pathomechanisms may contribute at least in part to the severe cardiac alterations characteristic of patients affected by these diseases.<\/jats:p>","DOI":"10.1111\/febs.13526","type":"journal-article","created":{"date-parts":[[2015,9,26]],"date-time":"2015-09-26T08:04:38Z","timestamp":1443254678000},"page":"4714-4726","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Deregulation of mitochondrial functions provoked by long\u2010chain fatty acid accumulating in long\u2010chain 3\u2010hydroxyacyl\u2010CoA dehydrogenase and mitochondrial permeability transition deficiencies in rat heart \u2013 mitochondrial permeability transition pore opening as a potential contributing pathomechanism of cardiac alterations in these disorders"],"prefix":"10.1111","volume":"282","author":[{"given":"Cristiane","family":"Cecatto","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 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda H.","family":"Hickmann","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 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00edlia D. 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