Reduced cerebral blood flow and metabolic rate trigger an adaptive mitochondrial remodeling program in a Down syndrome mouse model

Down syndrome (DS) is characterized by mitochondrial dysfunction, yet the extent of this impact on brain bioenergetics is not well understood. Utilizing a mouse model called Dp16(1)Yey/+ with ~115 extra copies of human chromosome 21 genes, researchers investigated brain-wide metabolic deficits in DS.

Through magnetic resonance imaging (MRI), the study found that Dp16 mice exhibit reduced cerebral blood flow and oxygen metabolic rate, with a more pronounced effect in males compared to females. Despite these metabolic reductions, mitochondrial respiratory capacity and ATP synthase activity remained largely intact across brain regions, although sex differences were observed.

Further analysis of gene expression revealed an upregulation of mitochondrial oxidative phosphorylation (OXPHOS) genes, indicating an adaptive response to meet bioenergetic demands. This mitochondrial remodeling program was most prominent in the male cortex and female cerebellum, suggesting a sex-specific response to metabolic stress.

Overall, the findings demonstrate that the metabolic dysfunction in DS mice triggers an adaptive mitochondrial remodeling program throughout the brain. However, this compensatory mechanism does not fully normalize the metabolic deficits in Dp16 mice. Integrating functional assessments at the organismal and tissue levels with transcriptomic changes provides a comprehensive view of the physiological perturbations and adaptations in the DS brain, which may contribute to phenotypic outcomes associated with the condition.