Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/85925
Type: Artigo de periódico
Title: Ethylmalonic Acid Induces Permeability Transition In Isolated Brain Mitochondria
Author: Cecatto C.
Amaral A.U.
Leipnitz G.
Castilho R.F.
Wajner M.
Abstract: Predominant accumulation of ethylmalonic acid (EMA) in tissues and biological fluids is a characteristic of patients affected by short chain acyl-CoA dehydrogenase deficiency and ethylmalonic encephalopathy. Neurological abnormalities are frequently found in these disorders, but the mechanisms underlying the brain injury are still obscure. Since hyperlacticacidemia is also found in many affected patients indicating a mitochondrial dysfunction; in the present work, we evaluated the in vitro and ex vivo effects of EMA plus Ca 2+ on mitochondrial integrity and redox balance in succinate-supported brain organelles. We verified that the evaluated parameters were disturbed only when EMA was associated with exogenous micromolar Ca 2+ concentrations. Thus, we found that this short chain organic acid plus Ca2+ dissipated the membrane potential and provoked mitochondrial swelling, as well as impaired the mitochondrial Ca2+ retention capacity, resulting in a rapid Ca2+ release and decreased NAD(P)H matrix content. In contrast, EMA was not able to stimulate mitochondrial hydrogen peroxide generation. We also observed that all these effects were prevented by the mitochondrial Ca2+ uptake inhibitor ruthenium red and the mitochondrial permeability transition (MPT) inhibitors cyclosporin A (CsA) and ADP. Furthermore, mitochondria isolated from rat brains after in vivo intrastriatal administration of EMA was more susceptible to Ca 2+-induced swelling, which was fully prevented by CsA and ADP. Finally, EMA significantly decreased striatal slice viability, which was attenuated by CsA. The data strongly indicate that EMA reduced the mitochondrial threshold for Ca2+-induced MPT reinforcing the role of this cation in EMA-induced disruption of mitochondrial bioenergetics. It is, therefore, presumed that EMA acting synergistically with Ca2+ compromises mitochondrial energy homeostasis in the central nervous system that may explain at least in part the neurologic alterations presented by patients with abnormal levels of this organic acid. © 2014 Springer Science+Business Media.
Editor: Springer New York LLC
Rights: fechado
Identifier DOI: 10.1007/s12640-014-9460-5
Address: http://www.scopus.com/inward/record.url?eid=2-s2.0-84903815990&partnerID=40&md5=92206d3f696e8bf4ae6c351a41aac424
Date Issue: 2014
Appears in Collections:Unicamp - Artigos e Outros Documentos

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