RESUMEN
Fragile X syndrome (FXS) is a genetic disorder that is characterized by a range of cognitive and behavioral deficits, including mild-moderate intellectual disability. The disease is characterized by an X-linked mutation of the Fmr1 gene, which causes silencing of the gene coding for fragile X mental retardation protein (FMRP), a translational regulator integral for neurodevelopment. Mitochondrial dysfunction has been recently associated with FXS, with reports of increases in oxidative stress markers, reactive oxygen species, and lipid peroxidation being present in the brain tissue. Astrocytes, a prominent glial cell within the central nervous system (CNS), play a large role in regulating oxidative homeostasis within the developing brain and dysregulation of astrocyte redox balance in FXS, which may contribute to oxidative stress. Astrocyte function and mitochondrial bioenergetics are significantly influenced by oxygen availability and circulating sex hormones; yet, these parameters are rarely considered during in vitro experimentation. Given that the brain normally develops in a range of hypoxic conditions and FXS is a sex-linked genetic disorder, we investigated how different oxygen levels (normoxic vs. hypoxic) and biological sex affected mitochondrial bioenergetics of astrocytes in FXS. Our results demonstrate that both mitochondrial respiration capacity and reactive oxygen species emission are altered with Fmr1 deletion in astrocytes and these changes were dependent upon both sexual dimorphism and oxygen availability.
Asunto(s)
Astrocitos/metabolismo , Metabolismo Energético/fisiología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/metabolismo , Mitocondrias/metabolismo , Caracteres Sexuales , Animales , Hipoxia de la Célula/fisiología , Células Cultivadas , Corteza Cerebral/metabolismo , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/antagonistas & inhibidores , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Mitocondrias/genética , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Astrocytes, glial cells within the brain, work to protect neurons during high levels of activity by maintaining oxidative homeostasis via regulation of energy supply and antioxidant systems. In recent years, mitochondrial dysfunction has been highlighted as an underlying factor of pathology in many neurological disorders. In animal studies of Fragile X Syndrome (FXS), the leading genetic cause of autism, higher levels of reactive oxygen species, lipid peroxidation, and protein oxidation within the brain indicates that mitochondria function is also altered in FXS. Despite their integral contribution to redox homeostasis within the CNS, the role of astrocytes on the occurrence or progression of neurodevelopmental disorders in this way is rarely considered. This study specifically examines changes to astrocyte mitochondrial function and antioxidant expression that may occur in FXS. Using the Fmr1 knockout (KO) mouse model, mitochondrial respiration and reactive oxygen species (ROS) emission were analyzed in primary cortical astrocytes. While mitochondrial respiration was similar between genotypes, ROS emission was significantly elevated in Fmr1 KO astrocytes. Notably, NADPH-oxidase 2 expression in Fmr1 KO astrocytes was also enhanced but only changes in catalase antioxidant enzyme expression were noted. Characterization of astrocyte factors involved in redox imbalance is invaluable to uncovering potential sources of oxidative stress in neurodevelopmental disorders and more specifically, the intercellular mechanisms that contribute to dysfunction in FXS.