Metabolite accumulation in VLCAD deficiency markedly disrupts mitochondrial bioenergetics and Ca2+ homeostasis in the heart.
FEBS J
; 285(8): 1437-1455, 2018 04.
Article
de En
| MEDLINE
| ID: mdl-29476646
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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Calcium
/
Maladies mitochondriales
/
Long-chain-acyl-CoA dehydrogenase
/
Métabolisme énergétique
/
Homéostasie
/
Erreurs innées du métabolisme lipidique
/
Mitochondries du myocarde
/
Maladies musculaires
/
Myocarde
Limites:
Animals
Langue:
En
Journal:
FEBS J
Sujet du journal:
BIOQUIMICA
Année:
2018
Type de document:
Article
Pays d'affiliation:
Brésil