Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesis

Neurobiology of Disease

Alexandra Latini¹  Moacir Wajner¹  Gabriela Casanova²  Silvia Olivera³  Luis Barbeito³  Anabel Fernandez⁴  Juan Carlos Rosillo⁴  Patricia Cassina⁵ 

[1] Biochemistry Department, Instituto de Ciencias Basicas da Saude (ICBS), Universidad Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil;Cellular Biology Section, School of Sciences, UdelaR, Montevideo, Uruguay;Cellular and Molecular Neurobiology Department, Instituto Clemente Estable (IIBCE), Montevideo, Uruguay;Comparative Neuroanatomy (IIBCE)-Associated Unit to the School of Sciences, Universidad de la Republica (UdelaR), Montevideo, Uruguay;Histology Department, School of Medicine, UdelaR, Montevideo, Uruguay;

关键词: Astrocyte proliferation;    Glutaric acidemia I;    Mitochondria dysfunction;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown