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

Mitochondrial dysfunction is a central feature of Down syndrome (DS), yet how trisomy 21 affects brain bioenergetics across scales-from gene transcription to cellular function to whole-brain metabolism-remains poorly understood. Here, we use the Dp16(1)Yey/+ (abbreviated Dp16) DS mouse model, which carries ~115 triplicated gene orthologs of human chromosome 21, to address this major knowledge gap and to provide direct in vivo evidence of brain-wide metabolic deficit in DS. Using magnetic resonance imaging (MRI) approaches, we show that Dp16 mice have reduced cerebral blood flow and metabolic rate of oxygen, with effects more pronounced in males than in females. Despite the suppression of cerebral metabolic rate, mitochondrial respiratory capacity and ATP synthase activity are largely preserved across brain regions, with sex differences noted. Transcriptomic analyses reveal marked upregulation of mitochondrial OXPHOS genes and the convergence of biological pathways related to proteostasis and mitochondrial function across brain regions, with male cortex and female cerebellum showing the biggest change. Collectively, our data suggest that a brain-wide metabolic deficit in Dp16 mice triggers an adaptive mitochondrial remodeling program across the brain to support bioenergetic demands. This compensatory response, however, is insufficient to normalize the metabolic dysfunction in Dp16 mice. Our findings underscore the value of integrating functional assessments at the organismal and tissue levels with transcriptomic changes to gain a systems view of physiologic perturbations and adaptations in the DS brain which may influence phenotypic outcomes.