Bioenergetics dysfunction and permeability transition induction triggered by fatty acids accumulated in VLCAD deficiency in a hepatocyte intact system and isolated mitochondria

Presented By:

Bianca Seminotti, PhD1,2*, Cristiane Cecatto, MSc1,2, Simone Magagnin Wajner, MD, PhD3, Alexandre Umpierrez Amaral, PhD4, Moacir Wajner, MD, PhD1,2,5

1Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, Brazil
2Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
3Departamento de Medicina Interna, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
4Departamento de Ciências Biológicas, Universidade Regional Integrada do Alto Uruguai e das Missões, Erechim, RS, Brazi
5Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

* e-mail: seminotti.bianca@gmail.com; Phone: +55 51 99114-4523

Background: Cis-5-tetradecenoic (Cis-5) and myristic (Myr) acids are accumulated in tissues of very long-chain acyl-CoA dehydrogenase (VLCAD) deficient patients who usually manifest recurrent rhabdomyolysis, cardiomyopathy and hepatopathy. Symptomatology is usually worsened during episodes of metabolic decompensation, in which the body concentrations of the accumulating metabolites rapidly increase, suggesting toxicity of these fatty acids.

Methods and results: In this study, we demonstrate for the first time that pathological concentrations (10-60 μM) of cis-5-tetradecenoic acid (Cis-5) and myristic acid (Myr), that most accumulate in VLCAD deficiency, decrease ADP-linked mitochondrial respiration, respiratory chain electron flow and ATP production in rat liver mitochondrial preparations. Cis-5 and Myr also increased resting respiration and induced mitochondrial swelling, cytochrome c release and mitochondrial permeability transition (MPT) pore opening in Ca2+- loaded mitochondria. It was also demonstrated that the deleterious effects of these fatty acids on bioenergetics occurred in an intact cell system consisting of cultured hepatocytes, validating therefore, the findings observed in isolated mitochondria.

Discussion: The present data strongly indicate that disruption of mitochondrial bioenergetics probably associated with MPT and caused by the major fatty acids accumulating in VLCAD deficiency may be involved in the liver dysfunction of the affected patients. Financial support: PROPESQ/UFRGS, FAPERGS, CNPq, CAPES.