Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome
Open accessAbstract
Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked MECP2 gene, which encodes a methyl-CpG binding transcriptional repressor. Using the Mecp2-null mouse (an animal model for RTT) and differential display, we found that mice with neurological symptoms overexpress the nuclear gene for ubiquinol-cytochrome c reductase core protein 1 (Uqcrc1). Chromatin immunoprecipitation demonstrated that MeCP2 interacts with the Uqcrc1 promoter. Uqcrc1 encodes a subunit of mitochondrial respiratory complex III, and isolated mitochondria from the Mecp2-null brain showed elevated respiration rates associated with respiratory complex III and an overall reduction in coupling. A causal link between Uqcrc1 gene overexpression and enhanced complex III activity was established in neuroblastoma cells. Our findings raise the possibility that mitochondrial dysfunction contributes to pathology of the Mecp2-null mouse and may contribute to the long-known resemblance between Rett syndrome and certain mitochondrial disorders.
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RTT patients have increased oxidative burden and abnormal mitochondrial structure.
“RTT patients have increased oxidative burden and abnormal mitochondrial structure, while RTT animal models have defects in the mitochondrial respiratory chain [23,26,200–202] and oxidative changes in the brain [203].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [200]
The Discussion (page unavailable) reports earlier findings of abnormal mitochondrial structure in biopsies from RTT patients. It does not report increased oxidative burden in RTT patients; its mention of oxidative stress concerns other human disorders. The paper’s own respiratory-chain findings concern a mouse model. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRTT animal models have defects in the mitochondrial respiratory chain.
“RTT patients have increased oxidative burden and abnormal mitochondrial structure, while RTT animal models have defects in the mitochondrial respiratory chain [23,26,200–202] and oxidative changes in the brain [203].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [200]
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Cites
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Rett syndrome: a neurological disorder with metabolic components
Kyle, S. M., Vashi, N., & Justice, M. J. (2018) · Open Biology · doi:10.1098/rsob.170216 · Cited by 213 · see citing works
Mitochondrial abnormalities in temporal lobe of autistic brain
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MeCP2 modulates gene expression pathways in astrocytes
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“…expression studies revealed gene alterations in RTT human and mouse samples (upregulation of ubiquinolcytochrome c reductase core protein 1 and downregulation of cytochrome c oxidase subunit 1) that may lead to mitochondrial respiratory chain defects (Kriaucionis et al., 2006; Gibson et al., 2010).”
BackgroundSu, H., Fan, W., Coskun, P. E., Vesa, J., Gold, J.-A., Jiang, Y.-H., Potluri, P., Procaccio, V., Acab, A., Weiss, J. H., et al. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2009.06.079 · Cited by 80 · see citing works
James, S. J., Shpyleva, S., Melnyk, S., Pavliv, O., & Pogribny, I. P. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.87 · Cited by 79 · see citing works
Genetic modifiers of MeCP2 function in Drosophila
Cukier, H. N., Perez, A. M., Collins, A. L., Zhou, Z., Zoghbi, H. Y., & Botas, J. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000179 · Cited by 73 · see citing works
Enhanced Hypoxia Susceptibility in Hippocampal Slices From a Mouse Model of Rett Syndrome
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Modulation of Brain Cholesterol Metabolism through CYP46A1 Overexpression for Rett Syndrome
Audouard, E., Khefif, N., Gillet-Legrand, B., Nobilleau, F., Bouazizi, O., Stanga, S., Despres, G., Alves, S., Lamazière, A., Cartier, N., et al. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16060756 · Cited by 7 · see citing works
- Authors
- Kriaucionis, S., Paterson, A., Curtis, J., Guy, J., MacLeod, N., & Bird, A.
- Affiliations
- Wellcome Trust Centre for Cell Biology, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JR, Scotland, United Kingdom
- University of Edinburgh (GB)
- Wellcome Centre for Cell Biology (GB)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-07-01
- Volume
- 26
- Issue
- 13
- Pages
- 5033-5042
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2104811636
- Cited by
- 219
- References
- 3
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 15 · 2020: 14 · 2019: 14 · 2018: 10 · 2017: 14 · 2016: 11 · 2015: 9 · 2014: 19 · 2013: 13 · 2012: 10
- FWCI
- 7.02
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust
- Darwin Trust of Edinburgh
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- Rett syndrome, MeCP2, UQCRC1, mitochondrial dysfunction, gene overexpression, promoter binding, mitochondrial respiration, mitochondrial coupling, neuroblastoma cells, mitochondrial disease
- MeSH terms
- Animals, Brain, Disease Models, Animal, Gene Expression Regulation, Mice, Mutant Strains, Mitochondria, Promoter Regions, Genetic, Electron Transport Complex III, Rett Syndrome, Transcriptional Activation, Mitochondrial Diseases, Chromatin Immunoprecipitation, Mice, Methyl-CpG-Binding Protein 2
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