Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesis
Glutaric (GA) and 3-hydroxyglutaric (OHGA) acids accumulate in glutaric acidemia I (GAI), a neurometabolic disease characterized by acute striatal degeneration and chronic progressive cortical atrophy. To explore the hypothesis that astrocytes are involved in GAI pathogenesis and targets of accumula...
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doaj-dbab6c5b50b840a6a55074a96095110a2021-03-20T04:56:31ZengElsevierNeurobiology of Disease1095-953X2008-12-01323528534Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesisSilvia Olivera0Anabel Fernandez1Alexandra Latini2Juan Carlos Rosillo3Gabriela Casanova4Moacir Wajner5Patricia Cassina6Luis Barbeito7Cellular and Molecular Neurobiology Department, Instituto Clemente Estable (IIBCE), Montevideo, UruguayComparative Neuroanatomy (IIBCE)-Associated Unit to the School of Sciences, Universidad de la Republica (UdelaR), Montevideo, UruguayBiochemistry Department, Instituto de Ciencias Basicas da Saude (ICBS), Universidad Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, BrazilComparative Neuroanatomy (IIBCE)-Associated Unit to the School of Sciences, Universidad de la Republica (UdelaR), Montevideo, UruguayCellular Biology Section, School of Sciences, UdelaR, Montevideo, UruguayBiochemistry Department, Instituto de Ciencias Basicas da Saude (ICBS), Universidad Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, BrazilHistology Department, School of Medicine, UdelaR, Montevideo, UruguayCellular and Molecular Neurobiology Department, Instituto Clemente Estable (IIBCE), Montevideo, Uruguay; Corresponding author. Cellular and Molecular Neurobiology Department (NBCM), Instituto de Investigaciones Biológicas Clemente Estable (IIBCE)-Institut Pasteur Montevideo, Av. Italia 3318, CP 11600, 2nd Floor Montevideo, Uruguay. Fax: +598 2 487 5461.Glutaric (GA) and 3-hydroxyglutaric (OHGA) acids accumulate in glutaric acidemia I (GAI), a neurometabolic disease characterized by acute striatal degeneration and chronic progressive cortical atrophy. To explore the hypothesis that astrocytes are involved in GAI pathogenesis and targets of accumulating metabolites, we determined the effects of GA and OHGA on cultured rat cortical astrocytes. Remarkably, both acids induced mitochondria depolarization and stimulated proliferation in confluent cultures without apparent cell toxicity. Newborn rats injected with GA systemically also showed increased cell proliferation in different brain regions. Most of the proliferating cells displayed markers of immature astrocytes. Antioxidant iron porphyrins prevented both mitochondria dysfunction and increased in vitro and in vivo proliferation, suggesting a role of oxidative stress in inducing astrocytosis. Taken together, the data suggest that mitochondrial dysfunction induced by GA metabolites causes astrocytes to adopt a proliferative phenotype, which may underlie neuronal loss, white matter abnormalities and macrocephalia characteristics of GAI.http://www.sciencedirect.com/science/article/pii/S0969996108002192Astrocyte proliferationGlutaric acidemia IMitochondria dysfunction |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Silvia Olivera Anabel Fernandez Alexandra Latini Juan Carlos Rosillo Gabriela Casanova Moacir Wajner Patricia Cassina Luis Barbeito |
spellingShingle |
Silvia Olivera Anabel Fernandez Alexandra Latini Juan Carlos Rosillo Gabriela Casanova Moacir Wajner Patricia Cassina Luis Barbeito Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesis Neurobiology of Disease Astrocyte proliferation Glutaric acidemia I Mitochondria dysfunction |
author_facet |
Silvia Olivera Anabel Fernandez Alexandra Latini Juan Carlos Rosillo Gabriela Casanova Moacir Wajner Patricia Cassina Luis Barbeito |
author_sort |
Silvia Olivera |
title |
Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesis |
title_short |
Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesis |
title_full |
Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesis |
title_fullStr |
Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesis |
title_full_unstemmed |
Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesis |
title_sort |
astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia i (gai) metabolites: possible implications for gai pathogenesis |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2008-12-01 |
description |
Glutaric (GA) and 3-hydroxyglutaric (OHGA) acids accumulate in glutaric acidemia I (GAI), a neurometabolic disease characterized by acute striatal degeneration and chronic progressive cortical atrophy. To explore the hypothesis that astrocytes are involved in GAI pathogenesis and targets of accumulating metabolites, we determined the effects of GA and OHGA on cultured rat cortical astrocytes. Remarkably, both acids induced mitochondria depolarization and stimulated proliferation in confluent cultures without apparent cell toxicity. Newborn rats injected with GA systemically also showed increased cell proliferation in different brain regions. Most of the proliferating cells displayed markers of immature astrocytes. Antioxidant iron porphyrins prevented both mitochondria dysfunction and increased in vitro and in vivo proliferation, suggesting a role of oxidative stress in inducing astrocytosis. Taken together, the data suggest that mitochondrial dysfunction induced by GA metabolites causes astrocytes to adopt a proliferative phenotype, which may underlie neuronal loss, white matter abnormalities and macrocephalia characteristics of GAI. |
topic |
Astrocyte proliferation Glutaric acidemia I Mitochondria dysfunction |
url |
http://www.sciencedirect.com/science/article/pii/S0969996108002192 |
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