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Metabolite accumulation in VLCAD deficiency markedly disrupts mitochondrial bioenergetics and Ca 2+ homeostasis in the heart

2018; Wiley; Volume: 285; Issue: 8 Linguagem: Inglês

10.1111/febs.14419

1742-4658

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 F. Castilho, Moacır Wajner,

ATP Synthase and ATPases Research

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 (ΔΨ m ), matrix NAD (P)H pool, Ca 2+ 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 Ca 2+ uptake blocker ruthenium red, fully prevented the Cis‐5‐ and Myr‐induced decrease in ΔΨ m in Ca 2+ ‐loaded mitochondria, suggesting, respectively, the induction of MPT pore opening and the contribution of Ca 2+ 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 Ca 2+ 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 Ca 2+ homeostasis may contribute to the cardiac manifestations observed in VLCAD deficiency.