Experimental evidence that fatty acids accumulating in VLCAD deficiency disrupt mitochondrial respiration in heart, liver and brain of young rats

Cristiane Cecatto MSc1*, Kálita dos Santos Godoy1, Alessandro Wajner PhD1, Mariana de Oliveira Vargas Schmit1, Roger Frigério Castilho MD, PhD2, Moacir Wajner MD, PhD1, Alexandre Umpierrez Amaral PhD1,3

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

2Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil

3Departamento de Ciências Biológicas, Universidade Regional Integrada do Alto Uruguai e das Missões, Erechim, RS, Brazil

* email: cecattoc@gmail.com; Tel: +55 51 981522692

Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) is the most frequent disease of β-oxidation of very long-chain fatty acids (14 to 20 carbons). The disorder
is biochemically characterized by predominant tissue accumulation of myristic (Myr – C14:0) and cis-5-tetradecenoic acids (Cis-5 – C14:1). Affected patients usually manifest cardiomyopathy, hepatopathy and rhabdomyolysis, especially during catabolic situations. Considering that the pathophysiology of this disorder is poorly established, we investigated the effects of Myr and Cis-5 on important parameters of mitochondrial respiration measured by oxygen consumption in organelles from heart, liver and brain   of young rats. Myr markedly increased state 4 respiration in mitochondria from all tissues at a similar magnitude, whereas Cis-5 only altered this parameter in the brain, indicating an uncoupling behavior for these fatty acids. Atractyloside was not able to prevent these alterations, making unlikely the involvement of the adenine nucleotide translocator. In addition, Myr markedly decreased state 3 and uncoupled respiration in mitochondria from all tissues, indicating a metabolic inhibition, with no effect of Cis-5. We also observed that Myr-induced inhibition of oxidative phosphorylation involved complex I activity, since it was more evident with NADH-linked substrates (pyruvate, malate and glutamate) in rat heart mitochondria. Taken together, our results indicate that Myr is more toxic to mitochondrial respiratory activity as compared to Cis-5, behaving as uncoupler and metabolic inhibitor of oxidative phosphorylation. It may be therefore presumed that lipotoxicity contributes to mitochondrial bioenergetics dysfunction and this may represent an important pathomechanism in VLCAD deficient patients.

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

Keywords: very long-chain acyl-CoA dehydrogenase deficiency; myristic acid;
cis-5- tetradecenoic acid; mitochondrial respiration.

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