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

The FEBS Journal
Cristiane CecattoMoacir Wajner

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...Continue Reading

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Citations

Sep 3, 2020·Cellular and Molecular Neurobiology·Graziela Schmitt Ribas, Carmen Regla Vargas
Nov 6, 2020·Journal of Zhejiang University. Science. B·Ting ChenPing-Ping Jiang
Jan 14, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Ana Cristina RoginskiAlexandre Umpierrez Amaral
Aug 27, 2021·Clinical and Translational Science·Rasmus StenlidMaria Halldin

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