Disruption of brain and liver mitochondrial function caused by cis-4-decenoic and decanoic acids but not by octanoylcarnitine and decanoylcarnitine: is L-carnitine supplementation protective to MCAD deficient patients?

Moacir Wajner 1,2*, Cristiane Cecatto1, Janaína Camacho da Silva1, Alessandro Wajner1, Kálita dos Santos Godoy1, Rafael Teixeira Ribeiro1, Alexandre Umpierrez Amaral1

1Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

2Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

* email: mwajner@ufrgs.br Tel: +55 51 99777161

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is biochemically characterized by predominant tissue accumulation of octanoic (OA), decanoic (DA) and cis-4-decenoic (cDA) acids, as well as by their carnitine by-products. Untreated patients present episodic encephalopathic crises with coma and seizures and biochemical liver alterations, whose pathophysiology is poorly known. We investigated the in vitro effects of OA, DA, cDA, octanoylcarnitine and decanoylcarnitine on important mitochondrial functions in rat brain and liver mitochondria. DA and particularly cDA increased state 4 respiration and diminished state 3 and uncoupled respiration, as well as RCR in both tissues, suggesting that these fatty acids behave as uncouplers and as metabolic inhibitors of oxidative phosphorylation. DA and cDA also markedly decreased mitochondrial membrane potential (Δψm), NAD(P)H content and capacity to retain Ca2+ in brain and liver, with the most pronounced effects of cDA. These biochemical alterations were totally prevented by the classical inhibitors of mitochondrial permeability transition (mPT) CsA and by ruthenium red in Ca2+-loaded mitochondria, indicating the involvement of mPT and the importance of mitochondrial Ca2+ concentrations, respectively. cDA also induced lipid peroxidation in brain and liver and increased hydrogen peroxide formation in brain mitochondria, indicating that lipid oxidative damage/oxidative stress may underlie some of the cDA-induced observed effects. Interestingly, octanoylcarnitine and decanoylcarnitine did not alter any of the tested parameters, suggesting no toxicity of these compounds. Our results suggest that DA and more prominently cDA impair important brain and liver mitochondrial functions, possibly contributing to the neuropathology and liver alterations of MCAD deficiency and that carnitine supplementation inducing medium chain acylcarnitine formation may be beneficial to the patients.

Financial support: We thank PROPESQ/UFRGS, FAPERGS and CNPq.