cis-4-decenoic acid provokes mitochondrial bioenergetic dysfunction in rat brain.
OBJECTIVE
In the present work we investigated the in vitro effect of cis-4-decenoic acid, the pathognomonic metabolite of medium-chain acyl-CoA dehydrogenase deficiency, on various parameters of bioenergetic homeostasis in rat brain mitochondria.


METHODS
Respiratory parameters determined by oxygen consumption were evaluated, as well as membrane potential, NAD(P)H content, swelling and cytochrome c release in mitochondrial preparations from rat brain, using glutamate plus malate or succinate as substrates. The activities of citric acid cycle enzymes were also assessed.


RESULTS
cis-4-decenoic acid markedly increased state 4 respiration, whereas state 3 respiration and the respiratory control ratio were decreased. The ADP/O ratio, the mitochondrial membrane potential, the matrix NAD(P)H levels and aconitase activity were also diminished by cis-4-decenoic acid. These data indicate that this fatty acid acts as an uncoupler of oxidative phosphorylation and as a metabolic inhibitor. cis-4-decenoic acid also provoked a marked mitochondrial swelling when either KCl or sucrose was used in the incubation medium and also induced cytochrome c release from mitochondria, suggesting a non-selective permeabilization of the inner mitochondrial membrane.


CONCLUSIONS
It is therefore presumed that impairment of mitochondrial homeostasis provoked by cis-4-decenoic acid may be involved in the brain dysfunction observed in medium-chain acyl-CoA dehydrogenase deficient patients.
Schuck
Patrícia Fernanda
PF
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Ferreira
Gustavo da Costa
Gda C
Tahara
Erich Birelli
EB
Klamt
Fábio
F
Kowaltowski
Alicia Juliana
AJ
Wajner
Moacir
M
D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D005229:Fatty Acids, Monounsaturated; C055444:4-decenoic acid; D009249:NADP; D045304:Cytochromes c; D042964:Acyl-CoA Dehydrogenase