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

作者：Olivera Silvia; Fernandez Anabel; Latini Alexandra; Rosillo Juan Carlos; Casanova Gabriela; Wajner Moacir; Cassina Patricia; Barbeito Luis^*

来源：Neurobiology of Disease, 2008, 32(3): 528-534.

DOI：10.1016/j.nbd.2008.09.011

• Astrocyte proliferation
• Glutaric acidemia I
• Mitochondria dysfunction

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.

• 出版日期2008-12