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Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I

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Abstract

Patients affected by glutaric aciduria type I (GA-I) show progressive cortical leukoencephalopathy whose pathogenesis is poorly known. In the present work, we exposed cortical astrocytes of wild-type (Gcdh +/+) and glutaryl-CoA dehydrogenase knockout (Gcdh −/−) mice to the oxidative stress inducer menadione and measured mitochondrial bioenergetics, redox homeostasis, and cell viability. Mitochondrial function (MTT and JC1-mitochondrial membrane potential assays), redox homeostasis (DCFH oxidation, nitrate and nitrite production, GSH concentrations and activities of the antioxidant enzymes SOD and GPx), and cell death (propidium iodide incorporation) were evaluated in primary cortical astrocyte cultures of Gcdh +/+ and Gcdh −/− mice unstimulated and stimulated by menadione. We also measured the pro-inflammatory response (TNFα levels, IL1-β and NF-ƙB) in unstimulated astrocytes obtained from these mice. Gcdh −/− mice astrocytes were more vulnerable to menadione-induced oxidative stress (decreased GSH concentrations and altered activities of the antioxidant enzymes), mitochondrial dysfunction (decrease of MTT reduction and JC1 values), and cell death as compared with Gcdh +/+ astrocytes. A higher inflammatory response (TNFα, IL1-β and NF-ƙB) was also observed in Gcdh −/− mice astrocytes. These data indicate a higher susceptibility of Gcdh −/− cortical astrocytes to oxidative stress and mitochondrial dysfunction, probably leading to cell death. It is presumed that these pathomechanisms may contribute to the cortical leukodystrophy observed in GA-I patients.

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Acknowledgments

We are grateful to the financial support of CNPq - 470236/2012-4, FAPERGS—10/0031-1, PROPESQ/UFRGS—PIBIC 27613, FINEP/IBN-Net—01.06.0842-00 and INCT-EN—573677/2008-5.

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  1. Departamento e PPG Bioquímica, ICBS/Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos N° 2600, Anexo, Porto Alegre, RS, CEP90035-003, Brazil

    Marília Danyelle Nunes Rodrigues, Bianca Seminotti, Ângela Zanatta, Aline de Mello Gonçalves, Bruna Bellaver, Alexandre Umpierrez Amaral, André Quincozes-Santos, Diogo Onofre Souza & Moacir Wajner

  2. Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA

    Stephen Irwin Goodman & Michael Woontner

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

    Moacir Wajner

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  1. Marília Danyelle Nunes Rodrigues
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  2. Bianca Seminotti
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  3. Ângela Zanatta
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This study was performed in strict accordance with the Principles of Laboratory Animal Care, National Institute of Health of United States of America, NIH, publication n° 85–23, revised in 2011, and approved by the Ethical Committee for the Care and Use of Laboratory Animals of Hospital de Clínicas de Porto Alegre.

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Rodrigues, M.D.N., Seminotti, B., Zanatta, Â. et al. Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I. Mol Neurobiol 54, 4795–4805 (2017). https://doi.org/10.1007/s12035-016-0023-z

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