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.

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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.

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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.

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Correspondence to Patrick F Chinnery.

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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)

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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

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