Clonal Expansion of Early to Mid-Life Mitochondrial DNA Point Mutations Drives Mitochondrial Dysfunction during Human Ageing

English version České info

Mitochondrial DNA (mtDNA) mutations have been shown to accumulate with age in a number of human stem cell populations and cause mitochondrial dysfunction within individual cells resulting in a cellular energy deficit. The dynamics by which mtDNA mutations occur and accumulate within individual cells (known as clonal expansion) is poorly understood. In particular we do not know when in the life-course these mtDNA mutations occur. Here we have measured mtDNA mutation frequency using three different techniques; Random Mutation Capture, which measures low level mutation frequency as an indirect measure of mutation rate, Next Generation Sequencing, which measures clonally expanded mtDNA mutation frequency, and mitochondrial enzyme histochemistry as a marker of clonally expanded mtDNA mutations, on colorectal mucosal biopsies obtained from 207 healthy participants aged 17–78 years. We show that, by 17 years of age, there is a substantial mtDNA point mutation burden and that clonal expansion of early to mid-life mtDNA mutations is likely to be the cause of mitochondrial dysfunction associated with ageing in the human colon.

Vyšlo v časopise: Clonal Expansion of Early to Mid-Life Mitochondrial DNA Point Mutations Drives Mitochondrial Dysfunction during Human Ageing. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004620
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004620

Souhrn

Zdroje

1. GreavesLC, TurnbullDM (2009) Mitochondrial DNA mutations and ageing. Biochim Biophys Acta 1790: 1015–1020.

2. FellousTG, IslamS, TadrousPJ, EliaG, KocherHM, et al. (2009) Locating the stem cell niche and tracing hepatocyte lineages in human liver. Hepatology 49: 1655–1663.

3. Muller-HockerJ (1990) Cytochrome c oxidase deficient fibres in the limb muscle and diaphragm of man without muscular disease: an age-related alteration. J Neurol Sci 100: 14–21.

4. Muller-HockerJ, SchneiderbangerK, StefaniFH, KadenbachB (1992) Progressive loss of cytochrome c oxidase in the human extraocular muscles in ageing–a cytochemical-immunohistochemical study. Mutat Res 275: 115–124.

5. TaylorRW, BarronMJ, BorthwickGM, GospelA, ChinneryPF, et al. (2003) Mitochondrial DNA mutations in human colonic crypt stem cells. J Clin Invest 112: 1351–1360.

6. Yu-Wai-ManP, Lai-CheongJ, BorthwickGM, HeL, TaylorGA, et al. (2010) Somatic mitochondrial DNA deletions accumulate to high levels in aging human extraocular muscles. Invest Ophthalmol Vis Sci 51: 3347–3353.

7. KhrapkoK (2011) The timing of mitochondrial DNA mutations in aging. Nat Genet 43: 726–727.

8. LinnaneAW, MarzukiS, OzawaT, TanakaM (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1: 642–645.

9. BlackwoodJK, WilliamsonSC, GreavesLC, WilsonL, RigasAC, et al. (2011) In situ lineage tracking of human prostatic epithelial stem cell fate reveals a common clonal origin for basal and luminal cells. J Pathol 225: 181–188.

10. FellousTG, McDonaldSA, BurkertJ, HumphriesA, IslamS, et al. (2009) A methodological approach to tracing cell lineage in human epithelial tissues. Stem Cells 27: 1410–1420.

11. McDonaldSA, GreavesLC, Gutierrez-GonzalezL, Rodriguez-JustoM, DeheragodaM, et al. (2008) Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology 134: 500–510.

12. ShinMG, KijigayaS, McCoyJPJr, LevinBC, YoungNS (2004) Marked mitochondrial DNA sequence heterogeneity in single CD34+ cell clones from normal adult bone marrow. Blood 103: 553–561.

13. ShinMG, KijigayaS, TarnowkaM, McCoyJPJr, LevinBC, et al. (2004) Mitochondrial DNA sequence heterogeneity in circulating normal human CD34 cells and granulocytes. Blood 103: 4466–4477.

14. GreavesLC, PrestonSL, TadrousPJ, TaylorRW, BarronMJ, et al. (2006) Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc Natl Acad Sci U S A 103: 714–719.

15. NooteboomM, JohnsonR, TaylorRW, WrightNA, LightowlersRN, et al. (2010) Age-associated mitochondrial DNA mutations lead to small but significant changes in cell proliferation and apoptosis in human colonic crypts. Aging Cell 9: 96–99.

16. SharplessNE, DePinhoRA (2007) How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8: 703–713.

17. KujothGC, HionaA, PughTD, SomeyaS, PanzerK, et al. (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309: 481–484.

18. TrifunovicA, WredenbergA, FalkenbergM, SpelbrinkJN, RovioAT, et al. (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423.

19. AhlqvistKJ, HamalainenRH, YatsugaS, UutelaM, TerziogluM, et al. (2012) Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab 15: 100–109.

20. ChenML, LoganTD, HochbergML, ShelatSG, YuX, et al. (2009) Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction. Blood 114: 4045–4053.

21. FoxRG, MagnessS, KujothGC, ProllaTA, MaedaN (2012) Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption. Am J Physiol Gastrointest Liver Physiol 302: G914–924.

22. NorddahlGL, PronkCJ, WahlestedtM, StenG, NygrenJM, et al. (2011) Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell 8: 499–510.

23. EricsonNG, KulawiecM, VermulstM, SheahanK, O'SullivanJ, et al. (2012) Decreased mitochondrial DNA mutagenesis in human colorectal cancer. PLoS Genet 8: e1002689.

24. VermulstM, BielasJH, KujothGC, LadigesWC, RabinovitchPS, et al. (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39: 540–543.

25. GreavesLC, BeadleNE, TaylorGA, CommaneD, MathersJC, et al. (2009) Quantification of mitochondrial DNA mutation load. Aging Cell 8: 566–572.

26. VijgJ (2000) Somatic mutations and aging: a re-evaluation. Mutat Res 447: 117–135.

27. HeY, WuJ, DressmanDC, Iacobuzio-DonahueC, MarkowitzSD, et al. (2010) Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 464: 610–614.

28. PayneBA, WilsonIJ, Yu-Wai-ManP, CoxheadJ, DeehanD, et al. (2013) Universal heteroplasmy of human mitochondrial DNA. Hum Mol Genet 22: 384–390.

29. SamuelsDC, LiC, LiB, SongZ, TorstensonE, et al. (2013) Recurrent tissue-specific mtDNA mutations are common in humans. PLoS Genet 9: e1003929.

30. BrandonMC, LottMT, NguyenKC, SpolimS, NavatheSB, et al. (2005) MITOMAP: a human mitochondrial genome database - 2004 update. Nucleic Acids Res 33: D611–613.

31. YaoYG, BandeltHJ, YoungNS (2007) External contamination in single cell mtDNA analysis. PLoS One 2: e681.

32. NoahTK, DonahueB, ShroyerNF (2011) Intestinal development and differentiation. Exp Cell Res 317: 2702–2710.

33. ShoubridgeEA (2000) Mitochondrial DNA segregation in the developing embryo. Hum Reprod 15 Suppl 2: 229–234.

34. GreavesLC, ElsonJL, NooteboomM, GradyJP, TaylorGA, et al. (2012) Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations. PLoS Genet 8: e1003082.

35. GreavesLC, BarronMJ, PlusaS, KirkwoodTB, MathersJC, et al. (2010) Defects in multiple complexes of the respiratory chain are present in ageing human colonic crypts. Exp Gerontol 45: 573–579.

36. BandyB, DavisonAJ (1990) Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Radic Biol Med 8: 523–539.

37. CollerHA, KhrapkoK, BodyakND, NekhaevaE, Herrero-JimenezP, et al. (2001) High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nat Genet 28: 147–150.

38. ElsonJL, SamuelsDC, TurnbullDM, ChinneryPF (2001) Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. Am J Hum Genet 68: 802–806.

39. KowaldA, KirkwoodTB (2013) Mitochondrial mutations and aging: random drift is insufficient to explain the accumulation of mitochondrial deletion mutants in short-lived animals. Aging Cell 12: 728–731.

40. AmeurA, StewartJB, FreyerC, HagstromE, IngmanM, et al. (2011) Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet 7: e1002028.

41. GreavesLC, BarronMJ, Campbell-ShielG, KirkwoodTB, TurnbullDM (2011) Differences in the accumulation of mitochondrial defects with age in mice and humans. Mech Ageing Dev 132: 588–591.

42. KennedySR, SalkJJ, SchmittMW, LoebLA (2013) Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet 9: e1003794.

43. WilliamsSL, MashDC, ZuchnerS, MoraesCT (2013) Somatic mtDNA mutation spectra in the aging human putamen. PLoS Genet 9: e1003990.

44. StewartJB, FreyerC, ElsonJL, WredenbergA, CansuZ, et al. (2008) Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol 6: e10.

45. FanW, WaymireKG, NarulaN, LiP, RocherC, et al. (2008) A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319: 958–962.

46. RossJM, StewartJB, HagstromE, BreneS, MourierA, et al. (2013) Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501: 412–415.

47. Finch C, Kirkwood TBL. (2000) Chance, Development and Ageing: Oxford University Press.

48. LangieSA, LaraJ, MathersJC (2012) Early determinants of the ageing trajectory. Best Pract Res Clin Endocrinol Metab 26: 613–626.

49. BiggerBW, LiaoAY, SergijenkoA, CoutelleC (2011) Trial and error: how the unclonable human mitochondrial genome was cloned in yeast. Pharm Res 28: 2863–2870.

50. SenecaS, VancampenhoutK, Van CosterR, SmetJ, LissensW, et al. (2014) Analysis of the whole mitochondrial genome: translation of the Ion Torrent Personal Genome Machine system to the diagnostic bench? Eur J Hum Genet E-pub ahead of print. doi:10.1038/ejhg.2014.49