Impairment of mitochondrial bioenergetics and permeability transition induction caused by major long-chain fatty acids accumulating in VLCAD deficiency in skeletal muscle as potential pathomechanisms of myopathy

Autor(es)

Cecatto, Cristiane ^[1] ; Amaral, Alexandre Umpierrez ^{[1, 2, 3]} ; Roginski, Ana Cristina ^[1] ; Castilho, Roger Frigerio ^[4] ; Wajner, Moacir ^{[5, 1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Fed Rio Grande do Sul, Inst Ciencias Basicas Saude, Programa Posgrad Ciencias Biol Bioquim, Porto Alegre, RS - Brazil

^[2] Univ Fed Rio Grande do Sul, Inst Ciencias Basicas Saude, Dept Bioquim, Rua Ramiro Barcelos 2600 Anexo, BR-90035003 Porto Alegre, RS - Brazil

^[3] Univ Reg Integrada Alto Uruguai & Missoes, Dept Ciencias Biol, Erechim, RS - Brazil

^[4] Univ Estadual Campinas, Fac Ciencias Med, Dept Patol Clin, Campinas, SP - Brazil

^[5] Hosp Clin Porto Alegre, Serv Genet Med, Porto Alegre, RS - Brazil

• Tipo de documento: Artigo Científico
• Fonte: TOXICOLOGY IN VITRO; v. 62, FEB 2020.
• Citações Web of Science: 3

Resumo

cis-5-Tetradecenoic (cis-5) and myristic (Myr) acids predominantly accumulate in patients affected by very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. They commonly manifest myopathy with muscular pain and rhabdomyolysis, whose underlying mechanisms are poorly known. Thus, in the present study we investigated the effects of cis-5 and Myr on mitochondrial bioenergetics and Ca2+ homeostasis in rat skeletal muscle. cis-5 and Myr decreased ADP-stimulated (state 3) and CCCP-stimulated (uncoupled) respiration, especially when mitochondria were supported by NADH-linked as compared to FADH(2)-linked substrates. In contrast, these fatty acids increased resting respiration (state 4). Similar effects were observed in skeletal muscle fibers therefore validating the data obtained with isolated mitochondria. Furthermore, cis-S and Myr markedly decreased mitochondrial membrane potential and Ca2+ retention capacity that were avoided by cyclosporin A plus ADP and ruthenium red, indicating that cis-5 and Myr induce mitochondrial permeability transition (MPT). Finally, docosanoic acid did not disturb mitochondria] homeostasis, indicating selective effects for Myr and cis-5. Taken together, our findings indicate that major long-chain fatty acids accumulating in VLCAD deficiency behave as metabolic inhibitors, uncouplers of oxidative phosphorylation and MPT inducers. It is presumed that these pathomechanisms contribute to the muscular symptoms and rhabdomyolysis observed in patients affected by VLCAD deficiency. (AU)

• Processo FAPESP: 17/17728-8 - Função e disfunção mitocondrial: implicações para o envelhecimento e doenças associadas
• Beneficiário: Aníbal Eugênio Vercesi
• Modalidade de apoio: Auxílio à Pesquisa - Temático