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Human Molecular Genetics Advance Access originally published online on July 27, 2005
Human Molecular Genetics 2005 14(17):2587-2594; doi:10.1093/hmg/ddi293
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Mitochondrial DNA segregation in hematopoietic lineages does not depend on MHC presentation of mitochondrially encoded peptides

Brendan J. Battersby, Margaret E. Redpath and Eric A. Shoubridge*

Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

* To whom correspondence should be addressed at: Department of Human Genetics, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec H3A 2B4, Canada. Tel: +1 5143981997; Fax: +1 5143981509; Email: eric{at}ericpc.mni.mcgill.ca

Received June 21, 2005; Accepted July 20, 2005

Mutations in mitochondrial DNA (mtDNA) are associated with a broad spectrum of clinical disorders. The segregation pattern of pathogenic mtDNAs is an important determinant of both the onset and the severity of the disease phenotype, but the mechanisms controlling mtDNA segregation remain poorly understood. To investigate this, we previously generated heteroplasmic mice containing two different mtDNA haplotypes and showed that BALB/c mtDNA was invariably selected over NZB mtDNA in blood and spleen. Here, we have characterized this process in hematopoietic tissues and tested whether it involves the presentation of mtDNA-encoded peptides by MHC class Ib molecules. Selection against NZB mtDNA was widespread across different hematopoietic cell lineages and proportional to heteroplasmy levels. Backcrossing heteroplasmic mice with CAST/Ei, a strain in which the MHC class Ib molecule H2-M3 is silent, completely abolished selection against NZB mtDNA in the spleen. To test whether this effect depended on an intact immune system, we generated heteroplasmic mice missing functional copies of Tap1, ß2m or Rag1 to impair presentation or recognition of mtDNA-encoded peptides. The kinetics of selection against NZB mtDNA were unaltered in these mice compared with their wild-type littermates. We conclude that mtDNA selection in hematopoietic tissues is not based on an immune mechanism, but likely involves metabolic signaling.


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