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

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 (LCHFAs) 3‐hy...

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Published in:	The FEBS journal Vol. 282; no. 24; pp. 4714 - 4726
Main Authors:	Cecatto, Cristiane, Hickmann, Fernanda H, Rodrigues, Marília D. N, Amaral, Alexandre U, Wajner, Moacir
Format:	Journal Article
Language:	English
Published:	England Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies 01-12-2015 Blackwell Publishing Ltd
Subjects:	3-hydroxyacyl-CoA dehydrogenase adenosine diphosphate adenosine triphosphate Adenosine Triphosphate - metabolism Animals beta oxidation brain calcium Calcium Channel Blockers - pharmacology calcium homeostasis Calcium Signaling - drug effects Cardiomyopathies - enzymology Cardiomyopathies - metabolism cardiomyopathy Cell Membrane Permeability - drug effects cyclosporine Dehydrogenases energy Enzyme Inhibitors - pharmacology Fatty acids Heart Homeostasis Humans Lipid Metabolism, Inborn Errors - enzymology Lipid Metabolism, Inborn Errors - metabolism long chain fatty acids Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase - deficiency Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase - metabolism long‐chain 3‐hydroxy fatty acid membrane potential Membrane Potential, Mitochondrial - drug effects metabolites mitochondria Mitochondria, Heart - drug effects Mitochondria, Heart - enzymology Mitochondria, Heart - metabolism mitochondrial bioenergetics Mitochondrial DNA mitochondrial membrane Mitochondrial Membrane Transport Proteins - metabolism Mitochondrial Membranes - drug effects Mitochondrial Membranes - metabolism Mitochondrial Myopathies - enzymology Mitochondrial Myopathies - metabolism mitochondrial permeability transition Mitochondrial Swelling - drug effects Mitochondrial Trifunctional Protein - deficiency Mitochondrial Trifunctional Protein - metabolism Myristic Acids - metabolism NAD (coenzyme) NADP - metabolism Nervous System Diseases - enzymology Nervous System Diseases - metabolism Organ Specificity oxidative phosphorylation Oxidative Phosphorylation - drug effects Palmitic Acids - metabolism pathogenesis patients Permeability rats Rats, Wistar Rhabdomyolysis - enzymology Rhabdomyolysis - metabolism ruthenium red long-chain 3-hydroxy fatty acid mitochondrial permeability transition calcium homeostasis heart mitochondrial bioenergetics
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Summary:	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 (LCHFAs) 3‐hydroxytetradecanoic acid (3HTA) and 3‐hydroxypalmitic acid (3HPA). Patients commonly present severe cardiomyopathy for which the pathogenesis is still poorly established. We investigated the effects of 3HTA and 3HPA, the major metabolites accumulating in these disorders, on important parameters of mitochondrial homeostasis in Ca²⁺‐loaded heart mitochondria. 3HTA and 3HPA significantly decreased mitochondrial membrane potential, the matrix NAD(P)H pool and Ca²⁺ retention capacity, and also induced mitochondrial swelling. These fatty acids also provoked a marked decrease of ATP production reflecting severe energy dysfunction. Furthermore, 3HTA‐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 Ca²⁺ uptake blocker, indicating that LCHFAs induced Ca²⁺‐dependent mPT pore opening. Milder effects only achieved at higher doses of LCHFAs were observed in brain mitochondria, implying a higher vulnerability of heart to these fatty acids. By contrast, 3HTA and docosanoic acids did not change mitochondrial homeostasis, indicating selective effects for monocarboxylic LCHFAs. The present data indicate that the major LCHFAs accumulating in mitochondrial trifunctional protein and long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiencies induce mPT pore opening, compromising Ca²⁺ 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.
Bibliography:	http://dx.doi.org/10.1111/febs.13526 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1742-464X 1742-4658
DOI:	10.1111/febs.13526