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Deregulation of mitochondrial functions provoked by long‐chain fatty acid accumulating in long‐chain 3‐hydroxyacyl‐CoA dehydrogenase and mitochondrial permeability transition deficiencies in rat heart – mitochondrial permeability transition pore opening as a potential contributing pathomechanism of cardiac alterations in these disorders
Author(s) -
Cecatto Cristiane,
Hickmann Fernanda H.,
Rodrigues Marília D. N.,
Amaral Alexandre U.,
Wajner Moacir
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13526
Subject(s) - mitochondrial permeability transition pore , mitochondrion , oxidative phosphorylation , biochemistry , beta oxidation , fatty acid , homeostasis , inner mitochondrial membrane , biology , chemistry , microbiology and biotechnology , programmed cell death , apoptosis
Mitochondrial trifunctional protein and long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiencies are fatty acid oxidation disorders biochemically characterized by tissue accumulation of long‐chain fatty acids and derivatives, including the monocarboxylic long‐chain 3‐hydroxy fatty acids ( LCHFA s) 3‐hydroxytetradecanoic acid (3 HTA ) and 3‐hydroxypalmitic acid (3 HPA ). Patients commonly present severe cardiomyopathy for which the pathogenesis is still poorly established. We investigated the effects of 3 HTA and 3 HPA , the major metabolites accumulating in these disorders, on important parameters of mitochondrial homeostasis in Ca 2+ ‐loaded heart mitochondria. 3 HTA and 3 HPA significantly decreased mitochondrial membrane potential, the matrix NAD (P)H pool and Ca 2+ retention capacity, and also induced mitochondrial swelling. These fatty acids also provoked a marked decrease of ATP production reflecting severe energy dysfunction. Furthermore, 3 HTA ‐induced mitochondrial alterations were completely prevented by the classical mitochondrial permeability transition (mPT) inhibitors cyclosporin A and ADP , as well as by ruthenium red, a Ca 2+ uptake blocker, indicating that LCHFA s induced Ca 2+ ‐dependent mPT pore opening. Milder effects only achieved at higher doses of LCHFA s were observed in brain mitochondria, implying a higher vulnerability of heart to these fatty acids. By contrast, 3 HTA and docosanoic acids did not change mitochondrial homeostasis, indicating selective effects for monocarboxylic LCHFA s. The present data indicate that the major LCHFA s accumulating in mitochondrial trifunctional protein and long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiencies induce mPT pore opening, compromising Ca 2+ 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.