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:

Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations

Abstract

There is emerging evidence that people with successfully treated HIV infection age prematurely, leading to progressive multi-organ disease1, but the reasons for this are not known. Here we show that patients treated with commonly used nucleoside analog anti-retroviral drugs progressively accumulate somatic mitochondrial DNA (mtDNA) mutations, mirroring those seen much later in life caused by normal aging2,3. Ultra-deep re-sequencing by synthesis, combined with single-cell analyses, suggests that the increase in somatic mutation is not caused by increased mutagenesis but might instead be caused by accelerated mtDNA turnover. This leads to the clonal expansion of preexisting age-related somatic mtDNA mutations and a biochemical defect that can affect up to 10% of cells. These observations add weight to the role of somatic mtDNA mutations in the aging process and raise the specter of progressive iatrogenic mitochondrial genetic disease emerging over the next decade.

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

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

Figure 1: COX (cytochrome c oxidase) deficiency in single skeletal muscle fibers.
Figure 2: Mitochondrial DNA analysis of single skeletal muscle fibers.
Figure 3: Proportional level of mt.δ4977 'common deletion' (CD) in homogenized skeletal muscle from HIV-infected subjects.
Figure 4: Ultra-deep re-sequencing by synthesis (UDS) of skeletal muscle mtDNA.
Figure 5: Simulations of the effects of partial mitochondrial DNA (mtDNA) replication failure caused by nucleoside analog (NRTI) exposure.

Similar content being viewed by others

References

  1. Effros, R.B. et al. Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin. Infect. Dis. 47, 542–553 (2008).

    Article  Google Scholar 

  2. Bua, E. et al. Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers. Am. J. Hum. Genet. 79, 469–480 (2006).

    Article  CAS  Google Scholar 

  3. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

    Article  CAS  Google Scholar 

  4. Brierley, E.J., Johnson, M.A., James, O.F. & Turnbull, D.M. Effects of physical activity and age on mitochondrial function. QJM 89, 251–258 (1996).

    Article  CAS  Google Scholar 

  5. Desquilbet, L. et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J. Gerontol. A Biol. Sci. Med. Sci. 62, 1279–1286 (2007).

    Article  Google Scholar 

  6. Oursler, K.K., Sorkin, J.D., Smith, B.A. & Katzel, L.I. Reduced aerobic capacity and physical functioning in older HIV-infected men. AIDS Res. Hum. Retroviruses 22, 1113–1121 (2006).

    Article  CAS  Google Scholar 

  7. Guaraldi, G. et al. Coronary aging in HIV-infected patients. Clin. Infect. Dis. 49, 1756–1762 (2009).

    Article  Google Scholar 

  8. Valcour, V. et al. Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort. Neurology 63, 822–827 (2004).

    Article  CAS  Google Scholar 

  9. Lim, S.E. & Copeland, W.C. Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J. Biol. Chem. 276, 23616–23623 (2001).

    Article  CAS  Google Scholar 

  10. McComsey, G.A. et al. Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS 19, 15–23 (2005).

    Article  CAS  Google Scholar 

  11. Côté, H.C. et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N. Engl. J. Med. 346, 811–820 (2002).

    Article  Google Scholar 

  12. Maagaard, A. et al. Mitochondrial (mt)DNA changes in tissue may not be reflected by depletion of mtDNA in peripheral blood mononuclear cells in HIV-infected patients. Antivir. Ther. 11, 601–608 (2006).

    CAS  PubMed  Google Scholar 

  13. Hayashi, J. et al. Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. Proc. Natl. Acad. Sci. USA 88, 10614–10618 (1991).

    Article  CAS  Google Scholar 

  14. Corral-Debrinski, M. et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat. Genet. 2, 324–329 (1992).

    Article  CAS  Google Scholar 

  15. 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. 43, 217–223 (1998).

    Article  CAS  Google Scholar 

  16. Fayet, G. et al. Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function. Neuromuscul. Disord. 12, 484–493 (2002).

    Article  Google Scholar 

  17. Pereira, L. et al. The diversity present in 5,140 human mitochondrial genomes. Am. J. Hum. Genet. 84, 628–640 (2009).

    Article  CAS  Google Scholar 

  18. Lee, H.C., Pang, C.Y., Hsu, H.S. & Wei, Y.H. Differential accumulations of 4,977 bp deletion in mitochondrial DNA of various tissues in human ageing. Biochim. Biophys. Acta 1226, 37–43 (1994).

    Article  CAS  Google Scholar 

  19. Chinnery, P.F. & Samuels, D.C. Relaxed replication of mtDNA: a model with implications for the expression of disease. Am. J. Hum. Genet. 64, 1158–1165 (1999).

    Article  CAS  Google Scholar 

  20. Wanrooij, S. et al. Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA. Nucleic Acids Res. 32, 3053–3064 (2004).

    Article  CAS  Google Scholar 

  21. Del Bo, R. et al. Remarkable infidelity of polymerase gammaA associated with mutations in POLG1 exonuclease domain. Neurology 61, 903–908 (2003).

    Article  CAS  Google Scholar 

  22. Elson, J.L., Samuels, D.C., Turnbull, D.M. & Chinnery, P.F. Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. Am. J. Hum. Genet. 68, 802–806 (2001).

    Article  CAS  Google Scholar 

  23. Cherry, C.L. et al. Tissue-specific associations between mitochondrial DNA levels and current treatment status in HIV-infected individuals. J. Acquir. Immune Defic. Syndr. 42, 435–440 (2006).

    Article  CAS  Google Scholar 

  24. Smyth, K. et al. Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993–2006. HIV Med. 8, 367–373 (2007).

    Article  CAS  Google Scholar 

  25. Diaz, F. et al. Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control. Nucleic Acids Res. 30, 4626–4633 (2002).

    Article  CAS  Google Scholar 

  26. Greaves, L.C. et al. Quantification of mitochondrial DNA mutation load. Aging Cell 8, 566–572 (2009).

    Article  CAS  Google Scholar 

  27. Kollberg, G. et al. Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations. Eur. J. Hum. Genet. 13, 463–469 (2005).

    Article  CAS  Google Scholar 

  28. World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: A Public Health Approach (2006).

  29. Durham, S.E., Samuels, D.C., Cree, L.M. & Chinnery, P.F. Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A→G. Am. J. Hum. Genet. 81, 189–195 (2007).

    Article  CAS  Google Scholar 

  30. Shieh, D.B. et al. Mitochondrial DNA alterations in blood of the humans exposed to N,N-dimethylformamide. Chem. Biol. Interact. 165, 211–219 (2007).

    Article  CAS  Google Scholar 

  31. Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 38, 515–517 (2006).

    Article  CAS  Google Scholar 

  32. Durham, S.E., Samuels, D.C. & Chinnery, P.F. Is selection required for the accumulation of somatic mitochondrial DNA mutations in post-mitotic cells? Neuromuscul. Disord. 16, 381–386 (2006).

    Article  CAS  Google Scholar 

  33. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

  34. Quinlan, A.R., Stewart, D.A., Stromberg, M.P. & Marth, G.T. Pyrobayes: an improved base caller for SNP discovery in pyrosequences. Nat. Methods 5, 179–181 (2008).

    Article  CAS  Google Scholar 

  35. He, Y. et al. Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 464, 610–614 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was support by grants from the Medical Research Council (B.A.I.P.), British Infection Society (B.A.I.P.), the Newcastle Healthcare Charity (D.A.P.), the UK National Institute for Health Research (NIHR) Biomedical Research Centre for Aging and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals National Health Service (NHS) Trust (P.F.C.) and the Wellcome Trust (P.F.C.). The authors thank G.L. Toms for the use of his containment level 3 facility, E.L.C. Ong, M.L. Schmid, U. Schwab and R. Pattman for access to their clinic cohorts, J. Coxhead (NewGene, Newcastle upon Tyne, UK) for assistance with Roche 454 FLX and D. Deehan for assistance with obtaining control muscle samples.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Patrick F Chinnery.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–4 and Supplementary Tables 1, 2 and 4. (PDF 558 kb)

Supplementary Table 3

UDS (Roche 454 FLX GS) outputs (PDF 1719 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Payne, B., Wilson, I., Hateley, C. et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat Genet 43, 806–810 (2011). https://doi.org/10.1038/ng.863

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.863

This article is cited by

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