METABOLIC BUFFERING BY ASTROCYTES SHAPES CORTICAL MATURATION UNDER MITOCHONDRIAL REDOX STRESS

Brain development involves dynamic changes in synapse formation and neural activity, which are accompanied by high energetic and redox demands. In the cerebral cortex, these processes extend into the postnatal period and require precise metabolic coordination to maintain redox balance and support circuit maturation. Mitochondrial NADPH serves as a central source of reducing power that sustains cellular redox homeostasis. However, how disruption of mitochondrial redox metabolism during development affects cell type-specific responses and circuit maturation in vivo remains poorly understood. To address this question, we generated a mouse model with neural lineage-specific impairment of mitochondrial NADPH production and examined postnatal cortical maturation. Impairment of mitochondrial NADPH homeostasis resulted in postnatal growth failure and early lethality, with profound cellular remodeling of the cerebral cortex. Single-nucleus RNA sequencing revealed marked changes in cellular composition, including expansion of astrocyte populations and a relative reduction in excitatory neuron populations. Notably, these astrocytes exhibited robust induction of transcriptional programs associated with glutamate handling, ion homeostasis, synapse-related pathways, and reactive aldehyde detoxification. These findings indicate that astrocytes utilize metabolic buffering responses to cope with mitochondrial redox stress, influencing regulation of the synaptic microenvironment and contributing to a reduced representation of excitatory neurons. Our study highlights mitochondrial NADPH as an important metabolic regulator of astrocyte-mediated cortical maturation during development.