Journal of Radiation Protection and Research

The Korean Association for Radiation Protection (대한방사선방어학회)
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MITOCHONDRIAL DNA DELETION AND IMPAIRMENT OF MITOCHONDRIAL BIOGENESIS ARE MEDIATED BY REACTIVE OXYGEN SPECIES IN IONIZING RADIATION-INDUCED PREMATURE SENESCENCE

  • Eom, Hyeon-Soo (Radiation Biotechnology Research Division, Korea Atomic Energy Research Institute) ;
  • Jung, U-Hee (Radiation Biotechnology Research Division, Korea Atomic Energy Research Institute) ;
  • Jo, Sung-Kee (Radiation Biotechnology Research Division, Korea Atomic Energy Research Institute) ;
  • Kim, Young-Sang (Department of Biochemistry, College of Natural Sciences, Chungnam National University)
  • Received : 2011.08.23
  • Accepted : 2011.09.23
  • Published : 2011.09.30
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Abstract

Mitochondrial DNA (mtDNA) deletion is a well-known marker for oxidative stress and aging, and contributes to harmful effects in cultured cells and animal tissues. mtDNA biogenesis genes (NRF-1, TFAM) are essential for the maintenance of mtDNA, as well as the transcription and replication of mitochondrial genomes. Considering that oxidative stress is known to affect mitochondrial biogenesis, we hypothesized that ionizing radiation (IR)-induced reactive oxygen species (ROS) causes mtDNA deletion by modulating the mitochondrial biogenesis, thereby leading to cellular senescence. Therefore, we examined the effects of IR on ROS levels, cellular senescence, mitochondrial biogenesis, and mtDNA deletion in IMR-90 human lung fibroblast cells. Young IMR-90 cells at population doubling (PD) 39 were irradiated at 4 or 8 Gy. Old cells at PD55, and H2O2-treated young cells at PD 39, were compared as a positive control. The IR increased the intracellular ROS level, senescence-associated ${\beta}$-galactosidase (SA-${\beta}$-gal) activity, and mtDNA common deletion (4977 bp), and it decreased the mRNA expression of NRF-1 and TFAM in IMR-90 cells. Similar results were also observed in old cells (PD 55) and $H_2O_2$-treated young cells. To confirm that a increase in ROS level is essential for mtDNA deletion and changes of mitochondrial biogenesis in irradiated cells, the effects of N-acetylcysteine (NAC) were examined. In irradiated and $H_2O_2$-treated cells, 5 mM NAC significantly attenuated the increases of ROS, mtDNA deletion, and SA-${\beta}$-gal activity, and recovered from decreased expressions of NRF-1 and TFAM mRNA. These results suggest that ROS is a key cause of IR-induced mtDNA deletion, and the suppression of the mitochondrial biogenesis gene may mediate this process.

Keywords

References

  1. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress‐activated signaling pathways : a unifying hypothesis of type 2 diabetes. Endocrine Review 2002;23:599-622. https://doi.org/10.1210/er.2001-0039
  2. Turrens JF. Mitochondrial formation of reactive oxygen species. The Journal of Physiology 2003;552: 335-344. https://doi.org/10.1113/jphysiol.2003.049478
  3. Kinjo T, Ham‐Terhune J, Peloponese JM, Jeang KT. Induction of reactive oxygen species by human T-cell leukemia virus type 1 tax correlates with DNA damage and expression of cellular senescence marker. Journal of Virology 2010;84:5431-5437. https://doi.org/10.1128/JVI.02460-09
  4. Taanman JW. The mitochondrial genome: structure, transcription, translation and replication. Biochimica et Biophysica Acta. 1999;1410:103-123. https://doi.org/10.1016/S0005-2728(98)00161-3
  5. Suematsu N, Tsutsui H, Wen J. Oxidative stress mediates tumor necrosis factor‐induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 2003;18:1418-1423.
  6. Ide T, Tsutsui H, Hayashidani S, Kang D, Suematsu N, Nakamura K, Utsumi H, Hamasaki H, Takeshita A. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circulation Research 2001;88:529-535. https://doi.org/10.1161/01.RES.88.5.529
  7. Ballinger SW, Patterson C, Knight‐Lozano CA, Burow DL, Conklin CA, Hu Z, Reuf J, Horaist C, Lebovitz R, Hunter GC, McIntyre K, Runge MS. Mitochondrial integrity and function in atherogenesis. Circulation 2002;106:544-549. https://doi.org/10.1161/01.CIR.0000023921.93743.89
  8. Lee CM, Chung SS, Kaczkowski JM, Weindruch R, Aiken JM. Multiple mitochondrial DNA deletions associated with age in skeletal muscle of rhesusmonkeys. Journal of Gerontology 1993;48B:201-205. https://doi.org/10.1093/geronj/48.6.B201
  9. Lu CY, Lee HC, Fahn HJ, Wei YH. Oxidative damage elicited by imbalance of free radical scavenging enzymes is associated with large scale mtDNA deletions in aging human skin. Mutation Research 1999;423:11-21. https://doi.org/10.1016/S0027-5107(98)00220-6
  10. Attardi G, Shatz G. Biogenesis of mitochondria. Annual Review of Cell Biology 1988;4:289-333. https://doi.org/10.1146/annurev.cb.04.110188.001445
  11. Liu CS, Tsai CS, Kuo CL, Chen HW, Lii CK, Ma YS, Wei YH. Oxidative stress‐related alterations of the copy number of mitochondrial DNA in human leukocytes. Free Radical Research 2003;37:1307-1317. https://doi.org/10.1080/10715760310001621342
  12. 12. Kanki T, Ohgaki K, Gaspari M, Gustafsson CM, Fukuoh A, Sasaki N, Hamasaki N, Kang D. Architectural role of mitochondrial transcription factor A in maintenance of human mitochondrial DNA. Molecular and Cell Biology 2004;24:9823-9834. https://doi.org/10.1128/MCB.24.22.9823-9834.2004
  13. Scarpulla RC. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochimica et Biophysica Acta 2002;1576:1-14. https://doi.org/10.1016/S0167-4781(02)00343-3
  14. Suliman HB, Carraway MS, Welty‐Wolf KE, Whorton AR, Piantadosi CA. Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor‐1. The Journal of Biological Chemistry 2003;278:41510-41518. https://doi.org/10.1074/jbc.M304719200
  15. Zhang KJ, Zhu Y, Sun HY, Huang LF, Fu JR, Liu WL. Mechanism of radiation induced premature senescence of bone marrow stromal cells : experiment with murine bone marrow stromal cells. Zhonghua Yi Xue Za Zi. 2006;86:3431-3434.
  16. Oh CW, Bump EA, Kin JS, Janigro D, Mayberg MR. Induction of a senescence‐like phenotype in bovine aortic endothelial cells by ionizing radiation. Radiation Research 2001;156:232-240. https://doi.org/10.1667/0033-7587(2001)156[0232:IOASLP]2.0.CO;2
  17. Berneburg M, Grether‐Beck S, Ku‐ rten V, Ruzicka T, Briviba K, Sies H. Singlet oxygen mediates the UVA‐induced generation of the photoaging‐associated mitochondrial common deletion. The Journal of Biological Chemistry 1999;274:15345-15349. https://doi.org/10.1074/jbc.274.22.15345
  18. Berneburg M, Plettenberg H, Medve‐Konig K, Pfahlberg A, Gers‐Barlag H, Gefeller O. Induction of the photoaging‐associated mitochondrial common deletion in vivo in normal human skin. The Journal of Investigative Dermatology 2004;122:1277-1283. https://doi.org/10.1111/j.0022-202X.2004.22502.x
  19. Prithivirajsingh S, Story MD, Bergh SA, Geara FB, Ang KK, Ismail SM, Stevens CW, Buchholz TA, Brock WA. Accumulation of the common mitochondrial DNA deletion induced by ionizing radiation. FEBS Letters 2004;571:227-232. https://doi.org/10.1016/j.febslet.2004.06.078
  20. Yang NC, Hu ML. A fluorimetric method using fluorescein di‐β‐D‐galacto‐pyranoside for quantifying the senescence‐associated β‐galactosidase activity in human foreskin fibroblast Hs68 cells. Analytical Biochemistry 2004;325:337-343. https://doi.org/10.1016/j.ab.2003.11.012
  21. Florence DC, Celine B, Thierry P, Veronique R, Francois E, Noelle N, Geraldine C, Bertrand F, Francoise de Longueville, Sophiee B, Jose R, Olivier T. Repeated exposure of human skin fibroblasts to UVB at subcytotoxic level triggers premature senescence through the TGF‐${\beta}1$ signaling pathway. Journal of Cell Science 2005;118:743-758. https://doi.org/10.1242/jcs.01651
  22. Dumont P, Burton M, Chen QM, Gonos ES, Frippiat C, Mazarati JM, Eliaers F, Remacle J, Toussaint O. Induction of replicative senescence biomarkers by sublethal oxidative stresses in normal human fibroblast. Free Radical Biology & Medicine 2000;28:361-373. https://doi.org/10.1016/S0891-5849(99)00249-X
  23. Perez de Arce K, Foncea R, Leighton F. Reactive oxygen species mediates homocysteine‐induced mitochondrial biogenesis in human endothelial cells: Modulation by antioxidants. Biochemical and Biophysical Research Communication 2005;328: 1103-1109.
  24. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelly C, Medrano EE, Linskens M, Rubeji I, Pereira‐Smith O, Peacocke M, Campisi J. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences of the United States of America 1995;92:9363-9367. https://doi.org/10.1073/pnas.92.20.9363
  25. Wei YH. Oxidative stress and mitochondrial DNA mutations in human aging. Proceeding of the Society for Experimental Biology and Medicine 1998;217:53-63. https://doi.org/10.3181/00379727-217-44205
  26. Chen Q, Ames BN. Senescence‐like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proceedings of the National Academy of Sciences of the United States of America 1994;91:4130-4134. https://doi.org/10.1073/pnas.91.10.4130
  27. Chen Q, Fischer A, Reagan JD, Yan LJ, Ames BN. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proceedings of the National Academy of Sciences of the United States of America 1995;92:4337-4341. https://doi.org/10.1073/pnas.92.10.4337
  28. Nisoli E, Clementi E, Carruba MO, Moncada S. Defective mitochondrial biogenesis : a hallmark of the high cardiovascular risk in the metabolic syndrome?. Circulation Research 2007;100:795-806. https://doi.org/10.1161/01.RES.0000259591.97107.6c
  29. Gutierrez J, Ballinger SW, Darley‐Usmar VM, Landar A. Free radicals, mitochondria, and oxidized lipids : the emerging role in signal transduction invascular cells. Circulation Research 2006;99:924-932. https://doi.org/10.1161/01.RES.0000248212.86638.e9
  30. Li N, Brun T, Cnop M, Cunha DA, Eizirik DL, Maechler P. Transient oxidative stress damages mitochondrial machinery inducing persistent ${\beta}‐cell$ dysfunction. The Journal of Biological Chemistry 2009;284:23602-23612. https://doi.org/10.1074/jbc.M109.024323
  31. Dong F, Li Q, Sreejayan N, Nunn JM, Ren J. Metallothionein prevents high‐fat diet‐induced cardiac contractile dysfunction. Diabetes 2007;56:2201-2212. https://doi.org/10.2337/db06-1596