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Methylmalonic acid administration induces DNA damage in rat brain and kidney

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Abstract

Accumulation of methylmalonic acid (MMA) in tissues and biological fluids is the biochemical hallmark of methylmalonic aciduria. Affected patients present renal failure and severe neurological findings. Considering that the underlying pathomechanisms of tissue damage are not yet understood, in the present work we assessed the in vivo e in vitro effects of MMA on DNA damage in brain and kidney, as well as on p53 and caspase 3 levels, in the presence or absence of gentamicin (acute renal failure model). For in vitro studies, tissue prisms were incubated in the presence of different concentrations of MMA and/or gentamicin for one hour. For in vivo studies, animals received a single injection of gentamicin (70 mg/kg) and/or three injections of MMA (1.67 μmol/g; 11 h interval between injections). The animals were killed 1 h after the last MMA injection. Controls received saline in the same volumes. DNA damage was analyzed by the comet assay. We found that MMA and gentamicin alone or combined in vitro increased DNA damage in cerebral cortex and kidney of rats. Furthermore, MMA administration increased DNA damage in both brain and kidney. Gentamicin per se induced DNA damage only in kidney, and the association of MMA plus gentamicin also caused DNA damage in cerebral cortex and kidney. On the other hand, p53 and caspase 3 levels were not altered by the administration of MMA and/or gentamicin. Our findings provide evidence that DNA damage may contribute to the neurological and renal damage found in patients affected by methylmalonic aciduria.

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Acknowledgments

This work was supported by Universidade do Extremo Sul Catarinense (UNESC), Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq), Fundação de Amparo à Pesquisa e Inovação de Santa Catarina (FAPESC), and Núcleo de Excelência em Neurociências de Santa Catarina (NENASC; PRONEX program CNPq/FAPESC).

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Laboratório de Biologia Celular e Molecular, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Vanessa M. Andrade, Daniela D. Leffa, Adriani P. Damiani & Giana Hainzenreder

  2. Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Avenida Universitária, 1105, Bloco S, Sala 6, Criciúma, SC, CEP 88806-000, Brazil

    Hugo S. Dal Pont, Gustavo C. Ferreira & Patrícia F. Schuck

  3. Laboratório de Bioenergética, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Giselli Scaini & Emilio L. Streck

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  1. Vanessa M. Andrade
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Correspondence to Patrícia F. Schuck.

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Andrade, V.M., Dal Pont, H.S., Leffa, D.D. et al. Methylmalonic acid administration induces DNA damage in rat brain and kidney. Mol Cell Biochem 391, 137–145 (2014). https://doi.org/10.1007/s11010-014-1996-4

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  • DOI: https://doi.org/10.1007/s11010-014-1996-4

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