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Molecular and Cellular Biology, July 2006, p. 5033-5042, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.01665-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome

Skirmantas Kriaucionis,1 Andrew Paterson,2 John Curtis,2 Jacky Guy,1 Nikki MacLeod,2 and Adrian Bird1*

Wellcome Trust Centre for Cell Biology, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JR, Scotland, United Kingdom,1 Division of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, Scotland, United Kingdom2

Received 26 August 2005/ Returned for modification 7 October 2005/ Accepted 5 April 2006

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.

* Corresponding author. Mailing address: The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, The King's Buildings, Edinburgh EH9 3JR, United Kingdom. Phone: 0131-650-5670. Fax: 0131-650-5379. E-mail: a.bird{at}ed.ac.uk.

Molecular and Cellular Biology, July 2006, p. 5033-5042, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.01665-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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