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

There is emerging evidence that people with successfully treated HIV infection age prematurely, leading to progressive multi-organ disease, 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 aging. 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.

[1]  J. Hayashi,et al.  Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[2]  L. Sandvik,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 , 2005, Antiviral therapy.

[3]  S. Salamat,et al.  Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers. , 2006, American journal of human genetics.

[4]  M. Beal,et al.  Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age , 1992, Nature Genetics.

[5]  W. Copeland,et al.  Differential Incorporation and Removal of Antiviral Deoxynucleotides by Human DNA Polymerase γ* , 2001, The Journal of Biological Chemistry.

[6]  P. Chinnery,et al.  Is selection required for the accumulation of somatic mitochondrial DNA mutations in post-mitotic cells? , 2006, Neuromuscular Disorders.

[7]  F. Christiansen,et al.  Accumulation of mitochondrial DNA mutations in human immunodeficiency virus-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors. , 2003, American journal of human genetics.

[8]  I. James,et al.  Tissue-Specific Associations Between Mitochondrial DNA Levels and Current Treatment Status in HIV-Infected Individuals , 2006, Journal of acquired immune deficiency syndromes.

[9]  Robert W. Taylor,et al.  High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease , 2006, Nature Genetics.

[10]  C. Hoppel,et al.  Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine , 2005, AIDS.

[11]  O. Selnes,et al.  Higher frequency of dementia in older HIV-1 individuals , 2004, Neurology.

[12]  J. Halter,et al.  Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[13]  J. Halter,et al.  Workshop on HIV Infection and Aging: What Is Known and Future Research Directions , 2008 .

[14]  E. Holme,et al.  Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations , 2005, European Journal of Human Genetics.

[15]  P. Harrigan,et al.  Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. , 2002, The New England journal of medicine.

[16]  N. Bresolin,et al.  Remarkable infidelity of polymerase γA associated with mutations in POLG1 exonuclease domain , 2003, Neurology.

[17]  P. Chinnery,et al.  Relaxed replication of mtDNA: A model with implications for the expression of disease. , 1999, American journal of human genetics.

[18]  Laura C. Greaves,et al.  Quantification of mitochondrial DNA mutation load , 2009, Aging cell.

[19]  M. Bayona-Bafaluy,et al.  Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control. , 2002, Nucleic acids research.

[20]  C. van Broeckhoven,et al.  Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA. , 2004, Nucleic acids research.

[21]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[22]  Ricardo Rocha,et al.  The diversity present in 5140 human mitochondrial genomes. , 2009, American journal of human genetics.

[23]  P. Chinnery,et al.  Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A-->G. , 2007, American journal of human genetics.

[24]  Gabor T. Marth,et al.  Pyrobayes: an improved base caller for SNP discovery in pyrosequences , 2008, Nature Methods.

[25]  D. Dressman,et al.  Heteroplasmic mitochondrial DNA mutations in normal and tumor cells , 2010, Nature.

[26]  G. Ligabue,et al.  Coronary aging in HIV-infected patients. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[27]  J. Margolick,et al.  HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[28]  H. C. Lee,et al.  Differential accumulations of 4,977 bp deletion in mitochondrial DNA of various tissues in human ageing. , 1994, Biochimica et biophysica acta.

[29]  J. Sorkin,et al.  Reduced aerobic capacity and physical functioning in older HIV-infected men. , 2006, AIDS research and human retroviruses.

[30]  D. Turnbull,et al.  Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. , 2001, American journal of human genetics.

[31]  D. Turnbull,et al.  Effects of physical activity and age on mitochondrial function. , 1996, QJM : monthly journal of the Association of Physicians.

[32]  P. Price,et al.  Prevalence of and risk factors for HIV‐associated neuropathy in Melbourne, Australia 1993–2006 , 2007, HIV medicine.

[33]  M. Fardeau,et al.  Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function , 2002, Neuromuscular Disorders.

[34]  D. Shieh,et al.  Mitochondrial DNA alterations in blood of the humans exposed to N,N-dimethylformamide. , 2007, Chemico-biological interactions.

[35]  Margaret A. Johnson,et al.  Role of mitochondrial DNA mutations in human aging: Implications for the central nervous system and muscle , 1998, Annals of neurology.

[36]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.