Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Nuclear genetic control of mitochondrial DNA segregation

Nature Genetics volume 33, pages 183–186 (2003)Cite this article

Abstract

Mammalian mitochondrial DNA (mtDNA) is a high copy-number, maternally inherited genome that codes for a small number of essential proteins involved in oxidative phosphorylation. Mutations in mtDNA are responsible for a broad spectrum of clinical disorders1. The segregation pattern of pathogenic mtDNA mutants is an important determinant of the nature and severity of mitochondrial disease, but it varies with the specific mutation, cell type and nuclear background and generally does not correlate well with mitochondrial dysfunction2,3,4,5,6,7,8,9,10,11. To identify nuclear genes that modify the segregation behavior of mtDNA, we used a heteroplasmic mouse model derived from two inbred strains (BALB/c and NZB; ref. 12), in which we had previously demonstrated tissue-specific and age-dependent directional selection for different mtDNA genotypes in the same mouse13. Here we show that this phenotype segregates in F2 mice from a genetic cross (BALB/c × CAST/Ei) and that it maps to at least three quantitative-trait loci (QTLs). Genome-wide scans showed linkage of the trait to loci on Chromosomes 2, 5 and 6, accounting for 16–35% of the variance in the trait, depending on the tissue and age of the mouse. This is the first genetic evidence for nuclear control of mammalian mtDNA segregation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Frequency distributions of NZB mtDNA heteroplasmy and relative fitness in the liver of F2 mice.
Figure 2: Analysis of the QTL on Chromosome 5.
Figure 3: Plot of the lod curves under a constrained model for the QTL on Chromosome 2 and a free model for the QTL on Chromosome 6 associated with directional selection of mtDNA in heteroplasmic F2 (BALB/c × CAST/Ei) mice.

Similar content being viewed by others

References

  1. DiMauro, S. & Schon, E.A. Mitochondrial DNA mutations in human disease. Am. J. Med. Genet. 106, 18–26 (2001).

    Article  CAS  Google Scholar 

  2. Larsson, N.G., Holme, E., Kristiansson, B., Oldfors, A. & Tulinius, M. Progressive increase of the mutated mitochondrial DNA fraction in Kearns–Sayre syndrome. Pediatr. Res. 28, 131–136 (1990).

    Article  CAS  Google Scholar 

  3. Boulet, L., Karpati, G. & Shoubridge, E.A. Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am. J. Hum. Genet. 51, 1187–1200 (1992).

    CAS  Google Scholar 

  4. Yoneda, M., Chomyn, A., Martinuzzi, A., Hurko, O. & Attardi, G. Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy. Proc. Natl. Acad. Sci. USA 89, 11164–11168 (1992).

    Article  CAS  Google Scholar 

  5. Kawakami, Y. et al. Mitochondrial myopathy with progressive decrease in mitochondrial tRNA(Leu)(UUR) mutant genomes. Ann. Neurol. 35, 370–373 (1994).

    Article  CAS  Google Scholar 

  6. Dunbar, D.R., Moonie, P.A., Jacobs, H.T. & Holt, I.J. Different cellular backgrounds confer a marked advantage to either mutant or wild-type mitochondrial genomes. Proc. Natl. Acad. Sci. USA 92, 6562–6566 (1995).

    Article  CAS  Google Scholar 

  7. Fu, K. et al. A novel heteroplasmic tRNAleu(CUN) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in skeletal muscle and suggests an approach to therapy. Hum. Mol. Genet. 5, 1835–1840 (1996).

    Article  CAS  Google Scholar 

  8. Weber, K. et al. A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am. J. Hum. Genet. 60, 373–380 (1997).

    CAS  Google Scholar 

  9. Dubeau, F., De Stefano, N., Zifkin, B.G., Arnold, D.L. & Shoubridge, E.A. Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedigree. Ann. Neurol. 47, 179–185 (2000).

    Article  CAS  Google Scholar 

  10. Tang, Y., Manfredi, G., Hirano, M. & Schon, E.A. Maintenance of human rearranged mitochondrial DNAs in long-term cultured transmitochondrial cell lines. Mol. Biol. Cell 11, 2349–2358 (2000).

    Article  CAS  Google Scholar 

  11. Rahman, S., Poulton, J., Marchington, D. & Suomalainen, A. Decrease of 3243 A to G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am. J. Hum. Genet. 68, 238–240 (2001).

    Article  CAS  Google Scholar 

  12. Jenuth, J.P., Peterson, A.C., Fu, K. & Shoubridge, E.A. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat. Genet. 14, 146–151 (1996).

    Article  CAS  Google Scholar 

  13. Jenuth, J.P., Peterson, A.C. & Shoubridge, E.A. Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat. Genet. 16, 93–95 (1997).

    Article  CAS  Google Scholar 

  14. Clayton, D.A. Replication of animal mitochondrial DNA. Cell 28, 693–705 (1982).

    Article  CAS  Google Scholar 

  15. Birky, C.W. Jr. The inheritance of genes in mitochondria and chloroplasts: laws, mechanisms, and models. Annu. Rev. Genet. 35, 125–148 (2001).

    Article  CAS  Google Scholar 

  16. Chinnery, P.F. et al. Nonrandom tissue distribution of mutant mtDNA. Am. J. Med. Genet. 85, 498–501 (1999).

    Article  CAS  Google Scholar 

  17. van den Ouweland, J.M. et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat. Genet. 1, 368–371 (1992).

    Article  CAS  Google Scholar 

  18. Petruzzella, V. et al. Extremely high levels of mutant mtDNAs co-localize with cytochrome c oxidase-negative ragged-red fibers in patients harboring a point mutation at nt 3243. Hum. Mol. Genet. 3, 449–454 (1994).

    Article  CAS  Google Scholar 

  19. de Stordeur, E., Solignac, M., Monnerot, M. & Mounolou, J.C. The generation of transplasmic Drosophila simulans by cytoplasmic injection: effects of segregation and selection on the perpetuation of mitochondrial DNA heteroplasmy. Mol. Gen. Genet. 220, 127–132 (1989).

    Article  CAS  Google Scholar 

  20. Flint, J. & Mott, R. Finding the molecular basis of quantitative traits: successes and pitfalls. Nat. Rev. Genet. 2, 437–445 (2001).

    Article  CAS  Google Scholar 

  21. Battersby, B.J. & Shoubridge, E.A. Selection of a mtDNA sequence variant in hepatocytes of heteroplasmic mice is not due to differences in respiratory chain function or efficiency of replication. Hum. Mol. Genet. 10, 2469–2479 (2001).

    Article  CAS  Google Scholar 

  22. Meeusen, S. et al. Mgm101p is a novel component of the mitochondrial nucleoid that binds DNA and is required for the repair of oxidatively damaged mitochondrial DNA. J. Cell Biol. 145, 291–304 (1999).

    Article  CAS  Google Scholar 

  23. Kaufman, B.A. et al. In organello formaldehyde crosslinking of proteins to mtDNA: identification of bifunctional proteins. Proc. Natl. Acad. Sci. USA 97, 7772–7777 (2000).

    Article  CAS  Google Scholar 

  24. Gross, N.J., Getz, G.S. & Rabinowitz, M. Apparent turnover of mitochondrial deoxyribonucleic acid and mitochondrial phospholipids in the tissues of the rat. J. Biol. Chem. 244, 1552–1562 (1969).

    CAS  Google Scholar 

  25. Rolink, A.G., Andersson, J. & Melchers, F. Characterization of immature B cells by a novel monoclonal antibody, by turnover and by mitogen reactivity. Eur. J. Immunol. 28, 3738–3748 (1998).

    Article  CAS  Google Scholar 

  26. Manly, K.F. & Olson, J.M. Overview of QTL mapping software and introduction to map manager QT. Mamm. Genome. 10, 327–334 (1999).

    Article  CAS  Google Scholar 

  27. Basten, C., Weir, B.S. & Zeng, Z.-B. QTL Cartographer: A Reference Manual and Tutorial for QTL Mapping. (Department of Statistics, North Carolina State University, Raleigh, North Carolina, 1997).

    Google Scholar 

  28. Churchill, G.A. & Doerge, R.W. Empirical threshold values for quantitative trait mapping. Genetics. 138, 963–971 (1994).

    CAS  Google Scholar 

  29. North, B.V., Curtis, D. & Sham, P.C. A note on the calculation of empirical P values from Monte Carlo procedures. Am. J. Hum. Genet. 71, 439–441 (2002).

    Article  CAS  Google Scholar 

  30. Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Malo, A. Suomalainen, K. Hastings, S. Leary, J. Caron and K. Morgan for discussion and N. Hanna and B. Lauzon for technical assistance. This work was supported by grants from the Canadian Institutes of Health Research and the Howard Hughes Medical Institute to E.A.S. E.A.S. is an international scholar of the Howard Hughes Medical Institute and a Senior Investigator of the Canadian Institutes of Health Research. B.J.B. is supported by a Doctoral Award from the Canadian Institutes of Health Research. J.C.L.-O. is supported by funds to K. Morgan from the Canadian Genetic Diseases Network of Centres of Excellence program.

Author information

Authors and Affiliations

  1. Montreal Neurological Institute and Department of Human Genetics, McGill University, 3801 University Street, Montreal, H3A 2B4, Quebec, Canada

    Brendan J. Battersby, J.C. Loredo-Osti & Eric A. Shoubridge

Authors
  1. Brendan J. Battersby
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J.C. Loredo-Osti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric A. Shoubridge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric A. Shoubridge.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Battersby, B., Loredo-Osti, J. & Shoubridge, E. Nuclear genetic control of mitochondrial DNA segregation. Nat Genet 33, 183–186 (2003). https://doi.org/10.1038/ng1073

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1073

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing