Metabolite accumulation in VLCAD deficiency markedly disrupts mitochondrial bioenergetics and Ca2+ homeostasis in the heart.

Abstract

We studied the effects of the major long-chain fatty acids accumulating in very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, namely cis-5-tetradecenoic acid (Cis-5) and myristic acid (Myr), on important mitochondrial functions in isolated mitochondria from cardiac fibers and cardiomyocytes of juvenile rats. Cis-5 and Myr at pathological concentrations markedly reduced mitochondrial membrane potential (ΔΨm ), matrix NAD(P)H pool, Ca2+ retention capacity, ADP- (state 3) and carbonyl cyanide 3-chlorophenyl hydrazine-stimulated (uncoupled) respiration, and ATP generation. By contrast, these fatty acids increased resting (state 4) respiration (uncoupling effect) with the involvement of the adenine nucleotide translocator because carboxyatractyloside significantly attenuated the increased state 4 respiration provoked by Cis-5 and Myr. Furthermore, the classical inhibitors of mitochondrial permeability transition (MPT) pore cyclosporin A plus ADP, as well as the Ca2+ uptake blocker ruthenium red, fully prevented the Cis-5- and Myr-induced decrease in ΔΨm in Ca2+ -loaded mitochondria, suggesting, respectively, the induction of MPT pore opening and the contribution of Ca2+ toward these effects. The findings of the present study indicate that the major long-chain fatty acids that accumulate in VLCAD deficiency disrupt mitochondrial bioenergetics and Ca2+ homeostasis, acting as uncouplers and metabolic inhibitors of oxidative phosphorylation, as well as inducers of MPT pore opening, in the heart at pathological relevant concentrations. It is therefore presumed that a disturbance of bioenergetics and Ca2+ homeostasis may contribute to the cardiac manifestations observed in VLCAD deficiency.

• Authors: Cristiane Cecatto, Alexandre Umpierrez Amaral, Janaína Camacho da Silva, Alessandro Wajner, Mariana de Oliveira Vargas Schimit, Lucas Henrique Rodrigues da Silva, Simone Magagnin Wajner, Ângela Zanatta, Roger Frigério Castilho, Moacir Wajner
• Journal: The FEBS journal (FEBS J) Vol. 285 Issue 8 Pg. 1437-1455 (04 2018) ISSN: 1742-4658 [Electronic] England
• PMID: 29476646 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Federation of European Biochemical Societies.

Chemical References

• Fatty Acids
• Adenosine Triphosphate
• Acyl-CoA Dehydrogenase, Long-Chain
• Calcium

Topics

• Acyl-CoA Dehydrogenase, Long-Chain (deficiency, metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Calcium (metabolism)
• Cell Line
• Congenital Bone Marrow Failure Syndromes
• Energy Metabolism
• Fatty Acids (metabolism)
• Homeostasis
• Lipid Metabolism, Inborn Errors (metabolism)
• Membrane Potential, Mitochondrial
• Mitochondria, Heart (metabolism)
• Mitochondrial Diseases (metabolism)
• Muscular Diseases (metabolism)
• Myocardium (cytology, metabolism)
• Oxidative Phosphorylation
• Oxygen Consumption
• Rats, Wistar