Red blood cell metabolism in Down syndrome: hints on metabolic derangements in aging

Culp‐Hill, Rachel; Zheng, Connie; Reisz, Julie A.; Smith, Keith P; Rachubinski, Angela L.; Nemkov, Travis; Butcher, Eric T.; Granrath, Ross E; Hansen, Kirk C.; Espinosa, Joaquín M.; D’Alessandro, Angelo

doi:10.1182/bloodadvances.2017011957

Cited by 26 publications

(24 citation statements)

References 32 publications

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“…In contrast, other metabolites associated with hypercoagulability, such as homocysteine (65) (which increases in Down syndrome, ref. 66), were decreased in patients with COVID-19. The latter may be explained by increased oxidant stress in patients with COVID-19, suggested by increased serum levels of methionine sulfoxide and cystine, along with decreased antioxidants, such as cysteine and taurine (67) (but, interestingly, not reduced glutathione).…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 87%

COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status

Thomas¹,

Stefanoni²,

Reisz³

et al. 2020

JCI Insight

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Section: L I N I C a L M E D I C I N Ementioning

confidence: 87%

COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status

Thomas¹,

Stefanoni²,

Reisz³

et al. 2020

JCI Insight

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484

558

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“…As already mentioned earlier, DS is characterized by an overexpression of genes on chromosome 21, in addition to an overall dysregulation of an even larger set of genes located on the other chromosomes (Letourneau et al 2014 ; Araya et al 2019 ; Culp-Hill et al 2017 ; Mao et al 2005 ). Among these, there are genes involved in oxidative phosphorylation (OXPHOS), including all five mitochondrial complex subunits, genes implicated in mitochondrial biogenesis, and more generally in the mitochondrial function.…”

Section: Gene Expression Proteomic and Metabolomic Profiling Of Ds Amentioning

confidence: 91%

“…Culp-Hill et al ( 2017 ) reported untargeted and targeted metabolomics datasets. Data were filtered for the age: 12 ≤ Age ≤ 54, in line with the original study.…”

Section: Gene Expression Proteomic and Metabolomic Profiling Of Ds Amentioning

confidence: 99%

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Pecze

Randi

Szabó

2020

Mol Med

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Clinical observations and preclinical studies both suggest that Down syndrome (DS) may be associated with significant metabolic and bioenergetic alterations. However, the relevant scientific literature has not yet been systematically reviewed. The aim of the current study was to conduct a meta-analysis of metabolites involved in bioenergetics pathways in DS to conclusively determine the difference between DS and control subjects. We discuss these findings and their potential relevance in the context of pathogenesis and experimental therapy of DS. Articles published before July 1, 2020, were identified by using the search terms “Down syndrome” and “metabolite name” or “trisomy 21” and “metabolite name”. Moreover, DS-related metabolomics studies and bioenergetics literature were also reviewed. 41 published reports and associated databases were identified, from which the descriptive information and the relevant metabolomic parameters were extracted and analyzed. Mixed effect model revealed the following changes in DS: significantly decreased ATP, CoQ10, homocysteine, serine, arginine and tyrosine; slightly decreased ADP; significantly increased uric acid, succinate, lactate and cysteine; slightly increased phosphate, pyruvate and citrate. However, the concentrations of AMP, 2,3-diphosphoglycerate, glucose, and glutamine were comparable in the DS vs. control populations. We conclude that cells of subjects with DS are in a pseudo-hypoxic state: the cellular metabolic and bio-energetic mechanisms exhibit pathophysiological alterations that resemble the cellular responses associated with hypoxia, even though the supply of the cells with oxygen is not disrupted. This fundamental alteration may be, at least in part, responsible for a variety of functional deficits associated with DS, including reduced exercise difference, impaired neurocognitive status and neurodegeneration.

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“…In the last few years, the advent of omics technologies revived interest around blood metabolism as a critical source of information to investigate derangements in system metabolism as a function of aging [29]. Recently, we reported the impact of aging on RBC metabolism in a cohort of 97 subjects, including individuals with Down syndrome, the most common human condition due to aneuploidy in the human population (one in ~700 live births in the United States) [30]. Of note, individuals with Down syndrome are more susceptible to several of the comorbidities associated with aging, including neurocognitive diseases (e.g., Alzheimer’s disease), several autoimmune and hematological cancers, pulmonary hypertension, and hearing and vision problems [31,32].…”

Section: Introductionmentioning

confidence: 99%

Parabiosis Incompletely Reverses Aging-Induced Metabolic Changes and Oxidant Stress in Mouse Red Blood Cells

et al. 2019

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Mature red blood cells (RBCs) not only account for ~83% of the total host cells in the human body, but they are also exposed to all body tissues during their circulation in the bloodstream. In addition, RBCs are devoid of de novo protein synthesis capacity and, as such, they represent a perfect model to investigate system-wide alterations of cellular metabolism in the context of aging and age-related oxidant stress without the confounding factor of gene expression. In the present study, we employed ultra-high-pressure liquid chromatography coupled with mass spectrometry (UHPLC–MS)-based metabolomics and proteomics to investigate RBC metabolism across age in male mice (6, 15, and 25 months old). We report that RBCs from aging mice face a progressive decline in the capacity to cope with oxidant stress through the glutathione/NADPH-dependent antioxidant systems. Oxidant stress to tryptophan and purines was accompanied by declines in late glycolysis and methyl-group donors, a potential compensatory mechanism to repair oxidatively damaged proteins. Moreover, heterochronic parabiosis experiments demonstrated that the young environment only partially rescued the alterations in one-carbon metabolism in old mice, although it had minimal to no impact on glutathione homeostasis, the pentose phosphate pathway, and oxidation of purines and tryptophan, which were instead aggravated in old heterochronic parabionts.

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Red blood cell metabolism in Down syndrome: hints on metabolic derangements in aging

Abstract: Key Points• The red blood cell metabolic signature of Down syndrome is identified• Trisomy 21 impacts red blood cell redox, amino acid, purine, and bile acid metabolism in an age-and sexdependent fashion.

Cited by 26 publications

References 32 publications

COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status

COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Parabiosis Incompletely Reverses Aging-Induced Metabolic Changes and Oxidant Stress in Mouse Red Blood Cells

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