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Brain Advance Access published online on February 23, 2005
Brain, doi:10.1093/brain/awh447
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received September 3, 2004
Revised January 18, 2005
Accepted January 19, 2005

Article

Isolation of transcriptomal changes attributable to LHON mutations and the cybridization process

Steven R. Danielson 1, Valerio Carelli 2, Guolin Tan 1, Andrea Martinuzzi 3, Anthony H. V. Schapira 4, Marja-Liisa Savontaus 5, and Gino A. Cortopassi 1*

1 Department of Molecular Biosciences, University of California Davis, Davis, CA
2 Department of Neurological Sciences, University of Bologna, Bologna, Italy
3 Scientific Institute Eugenio Medea, Conegliano Research Center, Conegliano, Italy
4 Department of Clinical Neurosciences, Royal Free Hospital and University College Medical School, London, UK
5 Departments of Medical Genetics and Biology, University of Turku, Turku, Finland

* To whom correspondence should be addressed.
Gino A. Cortopassi, E-mail: gacortopassi{at}ucdavis.edu


  Abstract

Summary Leber's hereditary optic neuropathy (LHON) is thought to be the most common disease resulting from mitochondrial DNA (mtDNA) point mutations, and transmitochondrial cytoplasmic hybrid (cybrid) cell lines are the most frequently used model for understanding the pathogenesis of mitochondrial disorders. We have used oligonucleotide microarrays and a novel study design based on shared transcripts to allocate transcriptomal changes into rho-zero-dependent, cybridization-dependent and LHON-dependent categories in these cells. The analysis indicates that the rho-zero process has the largest transcriptomal impact, followed by the cybridization process, and finally the LHON mutations. The transcriptomal impacts of the rho-zero and cybridization processes preferentially and significantly affect the mitochondrial compartment, causing upregulation of many transcripts involved in oxidative phosphorylation, presumably in response to the mtDNA depletion that occurs at the rho-zero step. Nine LHON-specific transcriptional alterations were shared among osteosarcoma cybrids and lymphoblasts bearing LHON mutations. Notably, the aldose reductase transcript was overexpressed in LHON cybrids and lymphoblasts. Aldose reductase is also overexpressed in diabetic retinopathy, leading to optic nerve and retinal complications. The LHON-specific increase in transcript level was confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR), and a western blot confirmed a higher level of aldose reductase in mutant mitochondria. One product of aldose reductase is sorbitol, which has been linked to osmotic stress, oxidative stress and optic neuropathy, and sorbitol levels were increased in LHON cybrids. If these results are confirmed in patient tissues, aldose reductase inhibitors could have some therapeutic value for LHON.

Keywords: Leber's hereditary optic neuropathy; cybrid; microarray; rho-zero; aldose reductase.
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