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

Muzna Saqib, Dylan C. SarveriD, Zhiliang WeiiD, Guang William WongiD

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In-depth summary

Claude Opus 5.5 · xhigh effort · 8 Nov 2026 · from the full text of version 1 (31 Oct 2026) · CC BY 4.0

In Dp16 Down syndrome mice, MRI shows reduced cerebral blood flow and oxygen metabolism (significant in males), while brain mitochondrial respiratory capacity stays largely intact and oxidative phosphorylation genes rise.

The authors note that evidence for mitochondrial defects in Down syndrome (DS) comes largely from in vitro systems, and that positron emission tomography in people with DS tracks only uptake of the glucose analog fluorodeoxyglucose, not oxygen use. Here MRI-measured whole-brain oxygen metabolism in Dp16 mice is linked to regional respirometry and bulk RNA-seq, presented as the first direct in vivo demonstration of reduced cerebral blood flow and oxygen metabolism in a DS animal model.

Key results

  1. ShownMale Dp16 mice have lower whole-brain cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) than wild-type littermates, with oxygen extraction unchanged. Females trend the same way but do not reach significance.

    11.7T MRI on 16-week-old mice, n = 12 per sex per genotype, Welch's t-test. Males: CBF and CMRO2 significantly reduced; respiration rate, brain volume and oxygen extraction fraction (OEF) not different. Females: CBF and CMRO2 lower but not significant; OEF and respiration rate unchanged; brain volume modestly larger. The text gives no effect sizes. · Reduced cerebral blood flow and metabolic rate…; DISCUSSION; Magnetic resonance imaging (MRI); Figure legends

  2. ShownEven though oxygen use is lower, maximal mitochondrial respiratory capacity in cortex, hippocampus, cerebellum and hypothalamus is mostly unchanged in Dp16 mice. A few sex- and region-specific shifts appear, mainly in ATP synthase hydrolytic activity.

    Seahorse assays on frozen tissue from 21-week-old mice, n = 8 per group, normalized to MitoTracker Deep Red. Males: higher complex I oxygen consumption in cerebellum, lower complex IV in hippocampus, higher ATP hydrolysis in cortex, hippocampus and cerebellum. Females: complexes I, II and IV unchanged; ATP hydrolysis lower in cortex and cerebellum. · Mitochondrial respiratory capacity across the…; Mitochondrial respirometry; Figure legends

  3. ShownBulk RNA-seq shows most triplicated genes expressed at levels consistent with their extra copy, and a sex- and region-specific response. Outside the hypothalamus, most nuclear-encoded oxidative phosphorylation (OXPHOS) genes go up while mtDNA-encoded complex I genes go down.

    Most triplicated genes at about 1.5-fold or more in all regions, some suppressed in female cerebellum and hippocampus. Up-regulated DEGs outnumbered down-regulated ones in every region; male cortex and female cerebellum had the most DEGs overall. Top upregulated GO terms in male cortex, both sexes' hippocampus and female cerebellum involved respiration and OXPHOS; mt-nd genes fell except in male hippocampus. · Increased expression dosage of triplicated genes…; The triplicated genes alter the brain…; Upregulation of mitochondrial OXPHOS genes…; RNA-sequencing and bioinformatics analysis

  4. SuggestedMitoCarta3.0 module scores put the largest mitochondrial transcriptional shifts in male cortex and female cerebellum, and the multi-region average shows nearly all nine modules raised in both sexes. Those two regions share an upregulated program enriched for translation and mitochondrial energy production.

    Nine modules (complexes I to V, Q-linked, cytochrome c, TCA, assembly factors); per-region Welch's t-tests with Holm-Sidak correction, but integrated scores were not tested. Translation, protein import, proteostasis, tRNA charging and redox modules also rose. Male cortex and female cerebellum shared 642 up and 313 down genes (|log2FC|>1, FDR<0.05). Enrichr found 44 terms for shared-up genes and none for shared-down. · Mitochondrial remodeling across the brain in…; Modular gene expression analysis across brain…; Secondary gene expression module analysis; Genome-wide differential expression and shared…

  5. ClaimedThe authors read the combined data as an adaptive mitochondrial remodeling program that keeps respiratory capacity but fails to restore oxygen metabolism. They propose that compensation of varying size likely contributes to the variable severity of DS phenotypes and to the differing survival of trisomic fetuses.

    This is an inference from three observations together: reduced CMRO2, preserved respirometry and raised mitochondrial gene expression. No experiment in the paper tests causality, measures protein levels or checks whether compensation differs between individuals. · Upregulation of mitochondrial OXPHOS genes…; Conserved mitochondrial-associated…; DISCUSSION

Methods, data and reproducibility

Dp16 and wild-type littermates of both sexes were scanned at 11.7T. T2-relaxation-under-spin-tagging MRI gave oxygen extraction fraction, phase-contrast MRI gave blood flow, and the Fick principle gave CMRO2. Four brain regions then underwent Seahorse respirometry on frozen tissue and bulk RNA-seq with DESeq2, GO enrichment and MitoCarta3.0 module scores.

  • Dp16 mice (about 115 triplicated Hsa21 orthologs) and wild-type littermates, C57BL/6J background, Jackson Laboratory strain 013530; in vivo MRI at 16 weeks of age · mouse · n = 12 per genotype per sex
  • Frozen cortex, hippocampus, cerebellum and hypothalamus from 21-week-old mice for Seahorse respirometry, three technical replicates per sample · mouse · n = WT = 8 and Dp16 = 8 per sex
  • Bulk RNA-seq (NovaSeq X Plus, 2 x 150 bp paired-end) of cortex, hippocampus, cerebellum and hypothalamus; hypothalamus data previously published · mouse · n = 72 samples stated; per-group n (8, or 6 for hypothalamus) implies 120 · PRJNA1463876 (Data Availability); PRJNA1160420 (Methods)
  • Mouse MitoCarta3.0 annotations used to define mitochondrial gene modules · mouse
Methods & tools
TRUST and phase-contrast MRI (11.7T Bruker Biospec), MATLAB (custom processing), Seahorse respirometry, MitoTracker Deep Red, Fastp, Hisat2, FeatureCounts, DESeq2, ClusterProfiler, Enrichr, Mouse MitoCarta3.0, GraphPad Prism 10
Reagents & environment
GraphPad Prism 10; reads aligned to GRCm39/mm39 with the standard Novogene pipeline (Fastp, Hisat2, FeatureCounts, DESeq2); Enrichr GO 2026 libraries; no versions given for the other tools; MRI processed with custom MATLAB tools.
Reproducibility gaps
RNA-seq is deposited in NCBI SRA (BioProject PRJNA1463876 in Data Availability; Methods gives PRJNA1160420), but no URL is printed. No link is given for the custom MATLAB TRUST and phase-contrast processing code. Raw MRI scan data are available only on request.
Limitations (6)
  • All mice were young (16 to 21 weeks), so whether Dp16 reproduces the progressive, age-linked fall in brain metabolism seen in people with DS is untested; the authors call for a longitudinal study. · stated by the authors
  • TRUST MRI gives only one whole-brain CMRO2 value and cannot resolve regional differences. In people with DS, fluorodeoxyglucose deficits concentrate in posterior cingulate and parietotemporal cortex. · stated by the authors
  • Respirometry on previously frozen tissue reports only maximal respiratory capacity of non-intact mitochondria, and subtle changes in supercomplex assembly cannot be fully excluded. · stated by the authors
  • Bulk-tissue RNA-seq cannot separate neuronal from glial contributions, and the analysis assumes that transcript changes track protein abundance. · stated by the authors
  • The readouts come from different ages and group sizes: MRI at 16 weeks with n = 12, respirometry at 21 weeks with n = 8, and RNA-seq given as 18 weeks in Results but 21 in Methods. The compensation model therefore rests on inference across assays, not on within-animal correlation or a causal test. · noted in this summary
  • The female CBF and CMRO2 decreases were not significant, and the integrated multi-region module scores were not tested statistically, yet both support the brain-wide conclusion. DEG thresholds also differ between hypothalamus (log2FC > 0.5) and the other regions (> 1). · noted in this summary

Read this if you study brain metabolism in Down syndrome or aneuploidy, or want an example of pairing in vivo MRI oxygen-metabolism measurements with regional respirometry and bulk RNA-seq in a mouse model.

Citations
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Abstract

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.

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