Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress
Open accessAbstract
A significant amount of reactive oxygen species (ROS) is generated during mitochondrial oxidative phosphorylation. Several studies have suggested that mtDNA may accumulate more oxidative DNA damage relative to nuclear DNA. This study used quantitative PCR to examine the formation and repair of hydrogen peroxide-induced DNA damage in a 16.2-kb mitochondrial fragment and a 17.7-kb fragment flanking the β-globin gene. Simian virus 40-transformed fibroblasts treated with 200 μM hydrogen peroxide for 15 or 60 min exhibited 3-fold more damage to the mitochondrial genome compared with the nuclear fragment. Following a 60-min treatment, damage to the nuclear fragment was completely repaired within 1.5 hr, whereas no DNA repair in the mitochondrion was observed. Mitochondrial function, as assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction, also showed a sharp decline. These cells displayed arrested-cell growth, large increases in p21 protein levels, and morphological changes consistent with apoptosis. In contrast, when hydrogen peroxide treatments were limited to 15 min, mtDNA damage was repaired with similar kinetics as the nuclear fragment, mitochondrial function was restored, and cells resumed division within 12 hr. These results indicate that mtDNA is a critical cellular target for ROS. A model is presented in which chronic ROS exposure, found in several degenerative diseases associated with aging, leads to decreased mitochondrial function, increased mitochondrial-generated ROS, and persistent mitochondrial DNA damage. Thus persistent mitochondrial DNA damage may serve as a useful biomarker for ROS-associated diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Unhealthy mitochondria emit higher levels of ROS, increasing oxidative stress and lipid peroxidation, and causing damage to mitochondrial and nuclear DNA.
“Beyond the oxidative stress generated as a byproduct of neuronal metabolism and the aberrant ROS production catalyzed by amyloid β peptide, there is also evidence that unhealthy mitochondria emit higher levels of ROS, increasing oxidative stress and lipid peroxidation, and causing damage to mitochondrial and nuclear DNA [60,61,62].”
From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [62]
The Discussion (page not provided) proposes that disruption of mitochondrial function could increase mitochondrial ROS and that lipid peroxidation could sustain DNA damage. The Results show damage to both mitochondrial and nuclear DNA after hydrogen peroxide exposure, but do not establish that ROS emitted by unhealthy mitochondria caused lipid peroxidation or the nuclear DNA damage. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Oxidative mechanisms in the toxicity of metal ions
Stohs, S. J., & Bagchi, D. (1995) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(94)00159-h · Cited by 4,219 · see citing works
Flagged first, then by citations
Research works printed but not linked: 5
- [7]Richter, C., Park, J.-W. & Ames, B. (1988) Proc. Natl. Acad. Sci. USA 85, 6465-6467.
- [10]Ames, B. N., Shigenaga, M. K. & Hagen, T. M. (1993) Proc. Natl. Acad. Sci. USA 90, 7915-7922.
- [11]Shigenaga, M., Hagen, T. M. & Ames, B. N. (1994) Proc. Natl. Acad. Sci. USA 91, 10771-10778.
- [13]Chen, Q. & Ames, B. (1994) Proc. Natl. Acad. Sci. USA 91, 4130-4134.
- [24]Yakes, F. M., Chen, Y. & Van Houten, B. (1996) in Technologies for Detection of DNA Damage and Mutations , ed. Pfeifer, G. P. (Plenum, New York), pp. 169-182.
Cited by
Sorted by citations
The Free Radical Theory of Aging Matures
BECKMAN, K. B., & AMES, B. N. (1998) · Physiological Reviews · doi:10.1152/physrev.1998.78.2.547 · Cited by 3,879 · see citing works
Selective degradation of mitochondria by mitophagy
Kim, I., Rodriguez-Enriquez, S., & Lemasters, J. J. (2007) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2007.03.034 · Cited by 1,558 · see citing works
Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling.
Lee, J., Giordano, S., & Zhang, J. (2012) · Biochemical Journal · doi:10.1042/bj20111451 · Cited by 1,438 · see citing works
Oxidative DNA damage and disease: induction, repair and significance
Evans, M. D., Dizdaroglu, M., & Cooke, M. S. (2004) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2003.11.001 · Cited by 1,372 · see citing works
Chronic inflammation and oxidative stress in human carcinogenesis
Federico, A., Morgillo, F., Tuccillo, C., Ciardiello, F., & Loguercio, C. (2007) · International Journal of Cancer · doi:10.1002/ijc.23192 · Cited by 1,001 · see citing works
Oxidation events and skin aging
Kammeyer, A., & Luiten, R. M. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.01.001 · Cited by 980 · see citing works
Mitochondrial damage induced by conditions of oxidative stress
Kowaltowski, A. J., & Vercesi, A. E. (1999) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(98)00216-0 · Cited by 866 · see citing works
Cross talk between mitochondria and NADPH oxidases
Dikalov, S. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.06.033 · Cited by 783 · see citing works
Free Radical Pathways in CNS Injury
LEWÉN, A., MATZ, P., & CHAN, P. H. (2000) · Journal of Neurotrauma · doi:10.1089/neu.2000.17.871 · Cited by 759 · see citing works
Role of mitochondria in oxidative stress and ageing
Lenaz, G. (1998) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(98)00120-0 · Cited by 650 · see citing works
Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials
Marzetti, E., Calvani, R., Cesari, M., Buford, T. W., Lorenzi, M., Behnke, B. J., & Leeuwenburgh, C. (2013) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.06.024 · Cited by 627 · see citing works
Caielli, S., Athale, S., Domic, B., Murat, E., Chandra, M., Banchereau, R., Baisch, J., Phelps, K., Clayton, S., Gong, M., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20151876 · Cited by 501 · see citing works
Vitamin C: Update on physiology and pharmacology
Mandl, J., Szarka, A., & Bánhegyi, G. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00282.x · Cited by 451 · see citing works
Trinei, M., Giorgio, M., Cicalese, A., Barozzi, S., Ventura, A., Migliaccio, E., Milia, E., Padura, I. M., Raker, V. A., Maccarana, M., et al. (2002) · Oncogene · doi:10.1038/sj.onc.1205513 · Cited by 436 · see citing works
Mitochondrial dysfunction in cardiovascular disease
Ballinger, S. W. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.02.014 · Cited by 405 · see citing works
Berneburg, M., Plettenberg, H., & Krutmann, J. (2000) · Photodermatology, Photoimmunology & Photomedicine · doi:10.1034/j.1600-0781.2000.160601.x · Cited by 403 · see citing works
Effects of ionizing radiation on mitochondria
Kam, W. W.-Y., & Banati, R. B. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.024 · Cited by 386 · see citing works
Use of H2O2 to Cause Oxidative Stress, the Catalase Issue
Ransy, C., Vaz, C., Lombès, A., & Bouillaud, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239149 · Cited by 347 · see citing works
Manganese Superoxide Dismutase: Guardian of the Powerhouse
Holley, A. K., Bakthavatchalu, V., Velez-Roman, J. M., & St. Clair, D. K. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms12107114 · Cited by 358 · see citing works
Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy
Calvani, R., Joseph, A.-M., Adhihetty, P. J., Miccheli, A., Bossola, M., Leeuwenburgh, C., Bernabei, R., & Marzetti, E. (2013) · bchm · doi:10.1515/hsz-2012-0247 · Cited by 328 · see citing works
DNA Polymerase γ in Mitochondrial DNA Replication and Repair
Graziewicz, M. A., Longley, M. J., & Copeland, W. C. (2006) · Chemical Reviews · doi:10.1021/cr040463d · Cited by 301 · see citing works
Cell-Free DNA as a Biomarker in Autoimmune Rheumatic Diseases
Duvvuri, B., & Lood, C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00502 · Cited by 282 · see citing works
Baud, O., Greene, A. E., Li, J., Wang, H., Volpe, J. J., & Rosenberg, P. A. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.3989-03.2004 · Cited by 292 · see citing works
Simmons, J. D., Lee, Y.-L., Mulekar, S., Kuck, J. L., Brevard, S. B., Gonzalez, R. P., Gillespie, M. N., & Richards, W. O. (2013) · Annals of Surgery · doi:10.1097/sla.0b013e3182a4ea46 · Cited by 259 · see citing works
Kowluru, R. A., Kowluru, V., Xiong, Y., & Ho, Y.-S. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.01.012 · Cited by 233 · see citing works
Novel DNA mismatch-repair activity involving YB-1 in human mitochondria
de Souza-Pinto, N. C., Mason, P. A., Hashiguchi, K., Weissman, L., Tian, J., Guay, D., Lebel, M., Stevnsner, T. V., Rasmussen, L. J., & Bohr, V. A. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.01.021 · Cited by 214 · see citing works
Joseph, A., Adhihetty, P. J., & Leeuwenburgh, C. (2016) · The Journal of Physiology · doi:10.1113/jp270659 · Cited by 186 · see citing works
Hajizadeh, S., DeGroot, J., TeKoppele, J. M., Tarkowski, A., & Collins, L. V. (2003) · Arthritis Res Ther · doi:10.1186/ar787 · Cited by 196 · see citing works
Induction of the Photoaging-Associated Mitochondrial Common Deletion In Vivo in Normal Human Skin
Berneburg, M., Plettenberg, H., Medve-König, K., Pfahlberg, A., Gers-Barlag, H., Gefeller, O., & Krutmann, J. (2004) · Journal of Investigative Dermatology · doi:10.1111/j.0022-202x.2004.22502.x · Cited by 193 · see citing works
Mitochondrial bioenergetics in aging
Lenaz, G., D’Aurelio, M., Merlo Pich, M., Genova, M. L., Ventura, B., Bovina, C., Formiggini, G., & Parenti Castelli, G. (2000) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(00)00177-8 · Cited by 189 · see citing works
Lu, C.-Y., Lee, H.-C., Fahn, H.-J., & Wei, Y.-H. (1999) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/s0027-5107(98)00220-6 · Cited by 186 · see citing works
Current Concepts of Neurodegenerative Mechanisms in Alzheimer’s Disease
Magalingam, K. B., Radhakrishnan, A., Ping, N. S., & Haleagrahara, N. (2018) · BioMed Research International · doi:10.1155/2018/3740461 · Cited by 178 · see citing works
Mitochondrial death effectors: Relevance to sarcopenia and disuse muscle atrophy
Marzetti, E., Hwang, J. C. Y., Lees, H. A., Wohlgemuth, S. E., Dupont-Versteegden, E. E., Carter, C. S., Bernabei, R., & Leeuwenburgh, C. (2010) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2009.05.007 · Cited by 174 · see citing works
Birch-Machin, M. A., & Swalwell, H. (2010) · Mutagenesis · doi:10.1093/mutage/gep061 · Cited by 159 · see citing works
Woodmansee, A. N., & Imlay, J. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203977200 · Cited by 152 · see citing works
Mitochondrial oxidative DNA damage and exposure to particulate air pollution in mother-newborn pairs
Grevendonk, L., Janssen, B. G., Vanpoucke, C., Lefebvre, W., Hoxha, M., Bollati, V., & Nawrot, T. S. (2016) · Environmental Health · doi:10.1186/s12940-016-0095-2 · Cited by 145 · see citing works
“be more extensive and persistent compared to nuclear DNA damage [30].”
BackgroundSarcopenia and cachexia: the adaptations of negative regulators of skeletal muscle mass
Sakuma, K., & Yamaguchi, A. (2012) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1007/s13539-011-0052-4 · Cited by 137 · see citing works
Li, N., Frigerio, F., & Maechler, P. (2008) · Biochemical Society Transactions · doi:10.1042/bst0360930 · Cited by 114 · see citing works
Reduction in frataxin causes progressive accumulation of mitochondrial damage
Karthikeyan, G. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg349 · Cited by 102 · see citing works
Zeng, X., & Rao, M. S. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2006.09.017 · Cited by 92 · see citing works
Rational therapeutic approaches to progressive supranuclear palsy
Stamelou, M., de Silva, R., Arias-Carrion, O., Boura, E., Hollerhage, M., Oertel, W. H., Muller, U., & Hoglinger, G. U. (2010) · Brain · doi:10.1093/brain/awq115 · Cited by 91 · see citing works
The impact of base excision DNA repair in age-related neurodegenerative diseases
Leandro, G. S., Sykora, P., & Bohr, V. A. (2015) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/j.mrfmmm.2014.12.011 · Cited by 72 · see citing works
Mitochondrial adaptations in skeletal muscle to hindlimb unloading
Wagatsuma, A., Kotake, N., Kawachi, T., Shiozuka, M., Yamada, S., & Matsuda, R. (2011) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-010-0677-1 · Cited by 70 · see citing works
Kruzel, M. L., Actor, J. K., Radak, Z., Bacsi, A., Saavedra-Molina, A., & Boldogh, I. (2010) · Innate Immunity · doi:10.1177/1753425909105317 · Cited by 69 · see citing works
Molecular and biochemical changes of the cardiovascular system due to smoking exposure
Armani, C., Landini Jr., L., & Leone, A. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209787846973 · Cited by 68 · see citing works
Yuzefovych, L. V., Pastukh, V. M., Ruchko, M. V., Simmons, J. D., Richards, W. O., & Rachek, L. I. (2019) · PLOS ONE · doi:10.1371/journal.pone.0222278 · Cited by 59 · see citing works
XPD localizes in mitochondria and protects the mitochondrial genome from oxidative DNA damage
Liu, J., Fang, H., Chi, Z., Wu, Z., Wei, D., Mo, D., Niu, K., Balajee, A. S., Hei, T. K., Nie, L., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv472 · Cited by 64 · see citing works
The lifecycle of skeletal muscle mitochondria in obesity
Pileggi, C. A., Parmar, G., & Harper, M. (2021) · Obesity Reviews · doi:10.1111/obr.13164 · Cited by 61 · see citing works
Bezdan, D., Grigorev, K., Meydan, C., Pelissier Vatter, F. A., Cioffi, M., Rao, V., MacKay, M., Nakahira, K., Burnham, P., Afshinnekoo, E., et al. (2020) · iScience · doi:10.1016/j.isci.2020.101844 · Cited by 59 · see citing works
Nuclear and mitochondrial DNA oxidation in Alzheimer's disease
Santos, R. X., Correia, S. C., Zhu, X., Lee, H.-G., Petersen, R. B., Nunomura, A., Smith, M. A., Perry, G., & Moreira, P. I. (2012) · Free Radical Research · doi:10.3109/10715762.2011.648188 · Cited by 57 · see citing works
Lee, H.-T., Lin, C.-S., Chen, W.-S., Liao, H.-T., Tsai, C.-Y., & Wei, Y.-H. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13078853 · Cited by 49 · see citing works
Do mtDNA deletions drive premature aging in mtDNA mutator mice?
Kraytsberg, Y., Simon, D. K., Turnbull, D. M., & Khrapko, K. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00484.x · Cited by 42 · see citing works
Mitochondria and Cellular Redox State on the Route from Ageing to Alzheimer's Disease
Abate, G., Vezzoli, M., Sandri, M., Rungratanawanich, W., Memo, M., & Uberti, D. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111385 · Cited by 41 · see citing works
Genome-wide mapping of genomic DNA damage: methods and implications
Amente, S., Scala, G., Majello, B., Azmoun, S., Tempest, H. G., Premi, S., & Cooke, M. S. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03923-6 · Cited by 33 · see citing works
Non-bulky Lesions in Human DNA: The Ways of Formation, Repair, and Replication
Ignatov, А. V., Bondarenko, K. A., & Makarova, A. V. (2017) · Acta Naturae · doi:10.32607/20758251-2017-9-3-12-26 · Cited by 31 · see citing works
Cardiovascular Health and Mitochondrial Function: Testing an Association
Zampino, M., Spencer, R. G., Fishbein, K. W., Simonsick, E. M., & Ferrucci, L. (2021) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glaa297 · Cited by 20 · see citing works
Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?
Hindle, A., Singh, S. P., Pradeepkiran, J. A., Bose, C., Vijayan, M., Kshirsagar, S., Sawant, N. A., & Reddy, P. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116098 · Cited by 14 · see citing works
Small peptides: Could they have a big role in metabolism and the response to exercise?
Atakan, M. M., Türkel, İ., Özerkliğ, B., Koşar, Ş. N., Taylor, D. F., Yan, X., & Bishop, D. J. (2024) · The Journal of Physiology · doi:10.1113/jp283214 · Cited by 13 · see citing works
YE, W., CHEN, S., JIN, S., & LU, J. (2013) · Molecular Medicine Reports · doi:10.3892/mmr.2013.1616 · Cited by 12 · see citing works
- Authors
- Yakes, F. M., & Van Houten, B.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Sealy Center for Molecular Science and Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77555-1068
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1997-01-21
- Volume
- 94
- Issue
- 2
- Pages
- 514-519
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC19544
- OpenAlex
- W1650754258
- Cited by
- 1,854
- References
- 1
- Citations by year
- 2026: 57 · 2025: 68 · 2024: 78 · 2023: 64 · 2022: 61 · 2021: 89 · 2020: 93 · 2019: 74 · 2018: 87 · 2017: 78 · 2016: 79 · 2015: 67 · 2014: 92 · 2013: 68 · 2012: 88
- FWCI
- 16.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences (R01ES007038, ES07281, ES-07038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- mitochondrial DNA damage, oxidative DNA damage, reactive oxygen species, hydrogen peroxide, oxidative stress, DNA repair, mitochondrial function, apoptosis, p21, aging, biomarkers, mitochondrial oxidative phosphorylation, SV40-transformed fibroblasts
- MeSH terms
- Cell Line, Cell Nucleus, DNA, DNA Damage, DNA Repair, DNA, Mitochondrial, Humans, Hydrogen Peroxide, Oxidation-Reduction, Apoptosis, Oxidative Stress
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
