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Ethylmalonic Acid Induces Permeability Transition in Isolated Brain Mitochondria

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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 Ca2+ 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 Ca2+ 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 Ca2+-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.

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Acknowledgments

The authors acknowledge the technical support of Edilene S. Santos. This work was supported by grants from CNPq, PRONEX II, FAPERGS, FAPESP (# 2011/50400-0), PROPESQ/UFRGS, FINEP research grant Rede Instituto Brasileiro de Neurociência (IBN-Net) # 01.06.0842-00, and Instituto Nacional de Ciência e Tecnologia Excitotoxicidade e Neuroproteção (INCT-EN).

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  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal de Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil

    Cristiane Cecatto, Alexandre Umpierrez Amaral, Guilhian Leipnitz & Moacir Wajner

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

    Moacir Wajner

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

    Roger Frigério Castilho

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  1. Cristiane Cecatto
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Correspondence to Moacir Wajner.

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Cecatto, C., Amaral, A.U., Leipnitz, G. et al. Ethylmalonic Acid Induces Permeability Transition in Isolated Brain Mitochondria. Neurotox Res 26, 168–178 (2014). https://doi.org/10.1007/s12640-014-9460-5

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