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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Apr;64(4):1158–1165. doi: 10.1086/302311

Relaxed replication of mtDNA: A model with implications for the expression of disease.

P F Chinnery 1, D C Samuels 1
PMCID: PMC1377840  PMID: 10090901

Abstract

Heteroplasmic mtDNA defects are an important cause of human disease with clinical features that primarily involve nondividing (postmitotic) tissues. Within single cells the percentage level of mutated mtDNA must exceed a critical threshold level before the genetic defect is expressed. Although the level of mutated mtDNA may alter over time, the mechanism behind the change is not understood. It currently is not possible to directly measure the level of mutant mtDNA within living cells. We therefore developed a mathematical model of human mtDNA replication, based on a solid foundation of experimentally derived parameters, and studied the dynamics of intracellular heteroplasmy in postmitotic cells. Our simulations show that the level of intracellular heteroplasmy can vary greatly over a short period of time and that a high copy number of mtDNA molecules delays the time to fixation of an allele. We made the assumption that the optimal state for a cell is to contain 100% wild-type molecules. For cells that contain pathogenic mutations, the nonselective proliferation of mutant and wild-type mtDNA molecules further delays the fixation of both alleles, but this leads to a rapid increase in the mean percentage level of mutant mtDNA within a tissue. On its own, this mechanism will lead to the appearance of a critical threshold level of mutant mtDNA that must be exceeded before a cell expresses a biochemical defect. The hypothesis that we present is in accordance with the available data and may explain the late presentation and insidious progression of mtDNA diseases.

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Selected References

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  1. Ankel-Simons F., Cummins J. M. Misconceptions about mitochondria and mammalian fertilization: implications for theories on human evolution. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13859–13863. doi: 10.1073/pnas.93.24.13859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Attardi G., Yoneda M., Chomyn A. Complementation and segregation behavior of disease-causing mitochondrial DNA mutations in cellular model systems. Biochim Biophys Acta. 1995 May 24;1271(1):241–248. doi: 10.1016/0925-4439(95)00034-2. [DOI] [PubMed] [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. 1992 Dec;51(6):1187–1200. [PMC free article] [PubMed] [Google Scholar]
  4. Brierley E. J., Johnson M. A., Lightowlers R. N., James O. F., Turnbull D. M. Role of mitochondrial DNA mutations in human aging: implications for the central nervous system and muscle. Ann Neurol. 1998 Feb;43(2):217–223. doi: 10.1002/ana.410430212. [DOI] [PubMed] [Google Scholar]
  5. Chinnery P. F., Turnbull D. M. Clinical features, investigation, and management of patients with defects of mitochondrial DNA. J Neurol Neurosurg Psychiatry. 1997 Nov;63(5):559–563. doi: 10.1136/jnnp.63.5.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clayton D. A. Mitochondrial DNA gets the drift. Nat Genet. 1996 Oct;14(2):123–125. doi: 10.1038/ng1096-123. [DOI] [PubMed] [Google Scholar]
  7. Flory P. J., Jr, Vinograd J. 5-bromodeoxyuridine labeling of monomeric and catenated circular mitochondrial DNA in HeLa cells. J Mol Biol. 1973 Feb 25;74(2):81–94. doi: 10.1016/0022-2836(73)90100-9. [DOI] [PubMed] [Google Scholar]
  8. 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. 1969 Mar 25;244(6):1552–1562. [PubMed] [Google Scholar]
  9. Hayashi J., Ohta S., Kikuchi A., Takemitsu M., Goto Y., Nonaka I. Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10614–10618. doi: 10.1073/pnas.88.23.10614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Howell N. mtDNA recombination: what do in vitro data mean? Am J Hum Genet. 1997 Jul;61(1):19–22. doi: 10.1086/513910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Johns D. R. Seminars in medicine of the Beth Israel Hospital, Boston. Mitochondrial DNA and disease. N Engl J Med. 1995 Sep 7;333(10):638–644. doi: 10.1056/NEJM199509073331007. [DOI] [PubMed] [Google Scholar]
  12. Larsson N. G., Clayton D. A. Molecular genetic aspects of human mitochondrial disorders. Annu Rev Genet. 1995;29:151–178. doi: 10.1146/annurev.ge.29.120195.001055. [DOI] [PubMed] [Google Scholar]
  13. 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. 1990 Aug;28(2):131–136. doi: 10.1203/00006450-199008000-00011. [DOI] [PubMed] [Google Scholar]
  14. Larsson N. G., Wang J., Wilhelmsson H., Oldfors A., Rustin P., Lewandoski M., Barsh G. S., Clayton D. A. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet. 1998 Mar;18(3):231–236. doi: 10.1038/ng0398-231. [DOI] [PubMed] [Google Scholar]
  15. Lightowlers R. N., Chinnery P. F., Turnbull D. M., Howell N. Mammalian mitochondrial genetics: heredity, heteroplasmy and disease. Trends Genet. 1997 Nov;13(11):450–455. doi: 10.1016/s0168-9525(97)01266-3. [DOI] [PubMed] [Google Scholar]
  16. Mita S., Schmidt B., Schon E. A., DiMauro S., Bonilla E. Detection of "deleted" mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9509–9513. doi: 10.1073/pnas.86.23.9509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Moraes C. T., Ricci E., Petruzzella V., Shanske S., DiMauro S., Schon E. A., Bonilla E. Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions. Nat Genet. 1992 Aug;1(5):359–367. doi: 10.1038/ng0892-359. [DOI] [PubMed] [Google Scholar]
  18. Poulton J., Morten K. Noninvasive diagnosis of the MELAS syndrome from blood DNA. Ann Neurol. 1993 Jul;34(1):116–116. doi: 10.1002/ana.410340124. [DOI] [PubMed] [Google Scholar]
  19. Schon E. A., Bonilla E., DiMauro S. Mitochondrial DNA mutations and pathogenesis. J Bioenerg Biomembr. 1997 Apr;29(2):131–149. doi: 10.1023/a:1022685929755. [DOI] [PubMed] [Google Scholar]
  20. Shoffner J. M. Maternal inheritance and the evaluation of oxidative phosphorylation diseases. Lancet. 1996 Nov 9;348(9037):1283–1288. doi: 10.1016/S0140-6736(96)09138-6. [DOI] [PubMed] [Google Scholar]
  21. Shoubridge E. A., Karpati G., Hastings K. E. Deletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease. Cell. 1990 Jul 13;62(1):43–49. doi: 10.1016/0092-8674(90)90238-a. [DOI] [PubMed] [Google Scholar]
  22. Shoubridge E. A. Mitochondrial DNA diseases: histological and cellular studies. J Bioenerg Biomembr. 1994 Jun;26(3):301–310. doi: 10.1007/BF00763101. [DOI] [PubMed] [Google Scholar]
  23. Tokunaga M., Mita S., Murakami T., Kumamoto T., Uchino M., Nonaka I., Ando M. Single muscle fiber analysis of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Ann Neurol. 1994 Apr;35(4):413–419. doi: 10.1002/ana.410350407. [DOI] [PubMed] [Google Scholar]
  24. Turnbull D. M., Lightowlers R. N. An essential guide to mtDNA maintenance. Nat Genet. 1998 Mar;18(3):199–200. doi: 10.1038/ng0398-199. [DOI] [PubMed] [Google Scholar]
  25. Wallace D. C. Diseases of the mitochondrial DNA. Annu Rev Biochem. 1992;61:1175–1212. doi: 10.1146/annurev.bi.61.070192.005523. [DOI] [PubMed] [Google Scholar]
  26. Wallace D. C., Shoffner J. M., Trounce I., Brown M. D., Ballinger S. W., Corral-Debrinski M., Horton T., Jun A. S., Lott M. T. Mitochondrial DNA mutations in human degenerative diseases and aging. Biochim Biophys Acta. 1995 May 24;1271(1):141–151. doi: 10.1016/0925-4439(95)00021-u. [DOI] [PubMed] [Google Scholar]
  27. Weber K., Wilson J. N., Taylor L., Brierley E., Johnson M. A., Turnbull D. M., Bindoff L. A. A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am J Hum Genet. 1997 Feb;60(2):373–380. [PMC free article] [PubMed] [Google Scholar]
  28. Zhang H., Cooney D. A., Sreenath A., Zhan Q., Agbaria R., Stowe E. E., Fornace A. J., Jr, Johns D. G. Quantitation of mitochondrial DNA in human lymphoblasts by a competitive polymerase chain reaction method: application to the study of inhibitors of mitochondrial DNA content. Mol Pharmacol. 1994 Dec;46(6):1063–1069. [PubMed] [Google Scholar]

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