Down syndrome is an oxidative phosphorylation disorder

Bayona‐Bafaluy, M. Pilar; Garrido-Pérez, Nuria; Meade, Patricia; Iglesias, Eldris; Jiménez-Salvador, Irene; Montoya, Julio; Martı́nez-Cué, Carmen; Ruiz‐Pesini, Eduardo

doi:10.1016/j.redox.2021.101871

Cited by 19 publications

(28 citation statements)

References 207 publications

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“…Oxidative stress and mitochondrial dysfunction are thought to play a critical role in DS and AD pathology (Mattson et al, 2008 ; Lott, 2012 ; Helguera et al, 2013 ; Izzo et al, 2018 ). Interestingly, a recent review postulates DS is an oxidative phosphorylation disorder (Bayona-Bafaluy et al, 2021 ). To date, the majority of studies evaluating oxidative phosphorylation and mitochondrial dysfunction in DS have used in vitro model systems.…”

Section: Discussionmentioning

confidence: 99%

“…Although the oxidative phosphorylation pathway is known to be dysregulated in DS (Helguera et al, 2013 ; Izzo et al, 2018 ; Bayona-Bafaluy et al, 2021 ) and changes in oxidative phosphorylation states have significant deleterious effects on normal neuronal function (Mattson et al, 2008 ), prior studies lack pathway-based evaluations conducted in vivo to understand mechanisms driving this critical pathology. Herein, we utilized the Ts65Dn mouse model to examine connectivity based degeneration deficits in two interconnected brain regions comprising the basocortical system, the BF and Fr Ctx, which are critically impacted in DS and AD and are reflective of age-related cognitive decline and loss of executive function.…”

Section: Introductionmentioning

confidence: 99%

“…BFCN degeneration begins at approximately 6 months of age (MO) in Ts65Dn mice, and loss of BFCNs and deficits in hippocampal cholinergic innervation are uniformly reported by ∼10 MO (Holtzman et al, 1996;Cooper et al, 2001;Hunter et al, 2003b;Contestabile et al, 2006;Powers et al, 2016). Many of the mitochondrial deficits reported in human DS, principally in the periphery (Izzo et al, 2018;Bayona-Bafaluy et al, 2021) are also present in this trisomic model including lower ATP production in vitro (Valenti et al, 2016) and metabolic changes in peripheral cell types (Cisterna et al, 2020). Further, genes postulated to be involved in mitochondrial dysfunction, including Dyrk1a and Ets2 (Izzo et al, 2018) are triplicated in human DS and reproduced in the Ts65Dn mouse model.…”

Section: Introductionmentioning

confidence: 99%

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Oxidative Phosphorylation Is Dysregulated Within the Basocortical Circuit in a 6-month old Mouse Model of Down Syndrome and Alzheimer’s Disease

Alldred

Lee

Stutzmann

et al. 2021

Front. Aging Neurosci.

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Down syndrome (DS) is the primary genetic cause of intellectual disability (ID), which is due to the triplication of human chromosome 21 (HSA21). In addition to ID, HSA21 trisomy results in a number of neurological and physiological pathologies in individuals with DS, including progressive cognitive dysfunction and learning and memory deficits which worsen with age. Further exacerbating neurological dysfunction associated with DS is the concomitant basal forebrain cholinergic neuron (BFCN) degeneration and onset of Alzheimer’s disease (AD) pathology in early mid-life. Recent single population RNA sequencing (RNA-seq) analysis in the Ts65Dn mouse model of DS, specifically the medial septal cholinergic neurons of the basal forebrain (BF), revealed the mitochondrial oxidative phosphorylation pathway was significantly impacted, with a large subset of genes within this pathway being downregulated. We further queried oxidative phosphorylation pathway dysregulation in Ts65Dn mice by examining genes and encoded proteins within brain regions comprising the basocortical system at the start of BFCN degeneration (6 months of age). In select Ts65Dn mice we demonstrate significant deficits in gene and/or encoded protein levels of Complex I-V of the mitochondrial oxidative phosphorylation pathway in the BF. In the frontal cortex (Fr Ctx) these complexes had concomitant alterations in select gene expression but not of the proteins queried from Complex I-V, suggesting that defects at this time point in the BF are more severe and occur prior to cortical dysfunction within the basocortical circuit. We propose dysregulation within mitochondrial oxidative phosphorylation complexes is an early marker of cognitive decline onset and specifically linked to BFCN degeneration that may propagate pathology throughout cortical memory and executive function circuits in DS and AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oxidative Phosphorylation Is Dysregulated Within the Basocortical Circuit in a 6-month old Mouse Model of Down Syndrome and Alzheimer’s Disease

Alldred

Lee

Stutzmann

et al. 2021

Front. Aging Neurosci.

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“…Defective mitochondrial bioenergetics negatively compromise neuronal development and represent an early event in developing the neurobiological alterations characterizing the syndrome [ 80 , 81 , 82 ]. Although DS is a multi-genic disorder and many pathways are affected, oxidative phosphorylation (OXPHOS) dysfunction was found ubiquitously present in any tissue or cell type, regardless of age, including fetal one, so that DS is now regarded as an OXPHOS disorder [ 83 ].…”

Section: Intercellular Mitochondrial Transfer In Different Pathophysiological Conditionsmentioning

confidence: 99%

Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer

Valenti

Vacca

Moro

et al. 2021

IJMS

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Mitochondria are complex intracellular organelles traditionally identified as the powerhouses of eukaryotic cells due to their central role in bioenergetic metabolism. In recent decades, the growing interest in mitochondria research has revealed that these multifunctional organelles are more than just the cell powerhouses, playing many other key roles as signaling platforms that regulate cell metabolism, proliferation, death and immunological response. As key regulators, mitochondria, when dysfunctional, are involved in the pathogenesis of a wide range of metabolic, neurodegenerative, immune and neoplastic disorders. Far more recently, mitochondria attracted renewed attention from the scientific community for their ability of intercellular translocation that can involve whole mitochondria, mitochondrial genome or other mitochondrial components. The intercellular transport of mitochondria, defined as horizontal mitochondrial transfer, can occur in mammalian cells both in vitro and in vivo, and in physiological and pathological conditions. Mitochondrial transfer can provide an exogenous mitochondrial source, replenishing dysfunctional mitochondria, thereby improving mitochondrial faults or, as in in the case of tumor cells, changing their functional skills and response to chemotherapy. In this review, we will provide an overview of the state of the art of the up-to-date knowledge on intercellular trafficking of mitochondria by discussing its biological relevance, mode and mechanisms underlying the process and its involvement in different pathophysiological contexts, highlighting its therapeutic potential for diseases with mitochondrial dysfunction primarily involved in their pathogenesis.

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“…Many genes and miRNAs located in chromosome 21 are known to be involved in mitochondrial pathways [ 21 , 22 , 23 , 24 ] and, therefore, might play a role in the mitochondrial impairment observed in DS. Interestingly, a recent review hypothesized that DS is an oxidative phosphorylation disorder [ 25 ], and another recent study proposed that the dysregulation within mitochondrial oxidative phosphorylation complexes is an early marker of cognitive decline in DS [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome

Zampieri

Costa

2022

Brain Sciences

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For many decades, neurons have been the central focus of studies on the mechanisms underlying the neurodevelopmental and neurodegenerative aspects of Down syndrome (DS). Astrocytes, which were once thought to have only a passive role, are now recognized as active participants of a variety of essential physiological processes in the brain. Alterations in their physiological function have, thus, been increasingly acknowledged as likely initiators of or contributors to the pathogenesis of many nervous system disorders and diseases. In this study, we carried out a series of real-time measurements of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in hippocampal astrocytes derived from neonatal Ts65Dn and euploid control mice using a Seahorse XFp Flux Analyzer. Our results revealed a significant basal OCR increase in neonatal Ts65Dn astrocytes compared with those from control mice, indicating increased oxidative phosphorylation. ECAR did not differ between the groups. Given the importance of astrocytes in brain metabolic function and the linkage between astrocytic and neuronal energy metabolism, these data provide evidence against a pure “neurocentric” vision of DS pathophysiology and support further investigations on the potential contribution of disturbances in astrocytic energy metabolism to cognitive deficits and neurodegeneration associated with DS.

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Down syndrome is an oxidative phosphorylation disorder

Cited by 19 publications

References 207 publications

Oxidative Phosphorylation Is Dysregulated Within the Basocortical Circuit in a 6-month old Mouse Model of Down Syndrome and Alzheimer’s Disease

Oxidative Phosphorylation Is Dysregulated Within the Basocortical Circuit in a 6-month old Mouse Model of Down Syndrome and Alzheimer’s Disease

Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer

Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome

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