Mitochondrial DNA segregation in hematopoietic lineages does not depend on MHC presentation of mitochondrially encoded peptides
Abstract
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, beta2m 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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Directional selection for one mtDNA genotype in certain tissues, mediated by single tissue-specific factors, has been repeatedly observed.
“However, the repeated observation of directional selection for one mtDNA genotype in certain tissues [170], mediated by single tissue-specific factors [171], suggests these mouse models will be particularly important in our quest to understanding the basis of tissue specificity and mtDNA somatic segregation.”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [171]
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Mitochondria: In Sickness and in Health
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“However, the repeated observation of directional selection for one mtDNA genotype in certain tissues [170], mediated by single tissue-specific factors [171], suggests these mouse models will be particularly”
Background
- Authors
- Battersby, B. J., Redpath, M. E., & Shoubridge, E. A.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- Corresponding author
- Battersby, Brendan J.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-07-27
- Volume
- 14
- Issue
- 17
- Pages
- 2587-2594
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2104456826
- Cited by
- 32
- References
- 34
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2015: 4 · 2014: 2 · 2013: 1 · 2012: 4
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McGill University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Keywords
- mitochondrial DNA segregation, heteroplasmy, MHC class Ib, hematopoietic lineage, TAP1, beta2m, RAG1, metabolic signaling, mitochondrial disease
- MeSH terms
- Aging, Animals, DNA, Mitochondrial, Haplotypes, Hematopoietic Stem Cells, Major Histocompatibility Complex, Mice, Inbred BALB C, Mice, Inbred Strains, Mitochondria, Chromosome Segregation, Mice
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