Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Career Basics

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 15 July 2005:
Vol. 309. no. 5733, pp. 481 - 484
DOI: 10.1126/science.1112125
Prev | Table of Contents | Next

Reports

Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging

G. C. Kujoth,1 A. Hiona,2 T. D. Pugh,3 S. Someya,4 K. Panzer,1 S. E. Wohlgemuth,2 T. Hofer,2 A. Y. Seo,2 R. Sullivan,5 W. A. Jobling,6 J. D. Morrow,7 H. Van Remmen,8 J. M. Sedivy,6 T. Yamasoba,9 M. Tanokura,4 R. Weindruch,3 C. Leeuwenburgh,2 T. A. Prolla1*

Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.

1 Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706, USA.
2 Department of Aging and Geriatric Research, College of Medicine, Institute on Aging, Biochemistry of Aging Laboratory, University of Florida, Gainesville, FL 32610-0107, USA.
3 Department of Medicine and Veterans Administration Hospital, University of Wisconsin, Madison, WI 53705-2286, USA.
4 Department of Applied Biological Chemistry, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
5 Waisman Center, University of Wisconsin, Madison, WI 53705-2280, USA.
6 Department of Molecular Biology, Cell Biology and Biochemistry and Center for Genomics and Proteomics, Brown University, Providence, RI 02912, USA.
7 Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
8 Department of Cellular and Structural Biology and Barshop Institute on Longevity and Aging Studies, University of Texas Health Center at San Antonio, San Antonio, TX 78284, USA.
9 Department of Otolaryngology, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.

* To whom correspondence should be addressed. E-mail: taprolla{at}wisc.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase.
G. Kronenberg, C. Harms, R. W. Sobol, F. Cardozo-Pelaez, H. Linhart, B. Winter, M. Balkaya, K. Gertz, S. B. Gay, D. Cox, et al. (2008)
J. Neurosci. 28, 7219-7230
   Abstract »    Full Text »    PDF »
Mitochondria as Chi.
D. C. Wallace (2008)
Genetics 179, 727-735
   Full Text »    PDF »
Expression and Maintenance of Mitochondrial DNA: New Insights into Human Disease Pathology.
G. S. Shadel (2008)
Am. J. Pathol. 172, 1445-1456
   Abstract »    Full Text »    PDF »
Mitochondrial DNA Content, an Inaccurate Biomarker of Mitochondrial Alteration in Human Immunodeficiency Virus-Related Lipodystrophy.
M. J. Kim, C. Jardel, C. Barthelemy, V. Jan, J. P. Bastard, S. Fillaut-Chapin, S. Houry, J. Capeau, and A. Lombes (2008)
Antimicrob. Agents Chemother. 52, 1670-1676
   Abstract »    Full Text »    PDF »
In Vivo Activation of Peroxisome Proliferator-Activated Receptor-{delta} Protects the Heart from Ischemia/Reperfusion Injury in Zucker Fatty Rats.
T.-L. Yue, S. S. Nerurkar, W. Bao, B. M. Jucker, L. Sarov-Blat, K. Steplewski, E. H. Ohlstein, and R. N. Willette (2008)
J. Pharmacol. Exp. Ther. 325, 466-474
   Abstract »    Full Text »    PDF »
mt-Nd2a Suppresses Reactive Oxygen Species Production by Mitochondrial Complexes I and III.
A. M. Gusdon, T. V. Votyakova, and C. E. Mathews (2008)
J. Biol. Chem. 283, 10690-10697
   Abstract »    Full Text »    PDF »
Differences in spontaneous mutation frequencies as a function of environmental stress in soil fungi at "Evolution Canyon," Israel.
B. C. Lamb, S. Mandaokar, B. Bahsoun, I. Grishkan, and E. Nevo (2008)
PNAS 105, 5792-5796
   Abstract »    Full Text »    PDF »
Mitochondrial Complex I Defect Induces ROS Release and Degeneration in Trabecular Meshwork Cells of POAG Patients: Protection by Antioxidants.
Y. He, K. W. Leung, Y.-H. Zhang, S. Duan, X.-F. Zhong, R.-Z. Jiang, Z. Peng, J. Tombran-Tink, and J. Ge (2008)
Invest. Ophthalmol. Vis. Sci. 49, 1447-1458
   Abstract »    Full Text »    PDF »
Trace amounts of 8-oxo-dGTP in mitochondrial dNTP pools reduce DNA polymerase {gamma} replication fidelity.
Z. F. Pursell, J. T. McDonald, C. K. Mathews, and T. A. Kunkel (2008)
Nucleic Acids Res. 36, 2174-2181
   Abstract »    Full Text »    PDF »
CAG repeat length variation in the polymerase gamma (POLG) gene: effect on semen quality.
G.H. Westerveld, L. Kaaij-Visser, M. Tanck, F. van der Veen, and S. Repping (2008)
Mol. Hum. Reprod. 14, 245-249
   Abstract »    Full Text »    PDF »
Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis.
C. Ricci, V. Pastukh, J. Leonard, J. Turrens, G. Wilson, D. Schaffer, and S. W. Schaffer (2008)
Am J Physiol Cell Physiol 294, C413-C422
   Abstract »    Full Text »    PDF »
Yeast mother cell-specific ageing, genetic (in)stability, and the somatic mutation theory of ageing.
P. Laun, C. V. Bruschi, J. Richard Dickinson, M. Rinnerthaler, G. Heeren, R. Schwimbersky, R. Rid, and M. Breitenbach (2007)
Nucleic Acids Res.
   Abstract »    Full Text »    PDF »
The ageing mitochondrial genome.
K. J. Krishnan, L. C. Greaves, A. K. Reeve, and D. Turnbull (2007)
Nucleic Acids Res. 35, 7399-7405
   Abstract »    Full Text »    PDF »
DNA damage, cellular senescence and organismal ageing: causal or correlative?.
J.-H. Chen, C. N. Hales, and S. E. Ozanne (2007)
Nucleic Acids Res. 35, 7417-7428
   Abstract »    Full Text »    PDF »
DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?.
J. F. Passos, G. Saretzki, and T. von Zglinicki (2007)
Nucleic Acids Res. 35, 7505-7513
   Abstract »    Full Text »    PDF »
A Measurable Increase in Oxidative Damage Due to Reduction in Superoxide Detoxification Fails to Shorten the Life Span of Long-Lived Mitochondrial Mutants of Caenorhabditis elegans.
W. Yang, J. Li, and S. Hekimi (2007)
Genetics 177, 2063-2074
   Abstract »    Full Text »    PDF »
2006 Kent Award Lecture: Is Cell Death and Replacement a Factor in Aging?.
H. R. Warner (2007)
J. Gerontol. A Biol. Sci. Med. Sci. 62, 1228-1232
   Abstract »    Full Text »    PDF »
Life and Death: Metabolic Rate, Membrane Composition, and Life Span of Animals.
A. J. Hulbert, R. Pamplona, R. Buffenstein, and W. A. Buttemer (2007)
Physiol Rev 87, 1175-1213
   Abstract »    Full Text »    PDF »
The Mitochondrial Transcription Factor TFAM Coordinates the Assembly of Multiple DNA Molecules into Nucleoid-like Structures.
B. A. Kaufman, N. Durisic, J. M. Mativetsky, S. Costantino, M. A. Hancock, P. Grutter, and E. A. Shoubridge (2007)
Mol. Biol. Cell 18, 3225-3236
   Abstract »    Full Text »    PDF »
Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease.
H. Fukui, F. Diaz, S. Garcia, and C. T. Moraes (2007)
PNAS 104, 14163-14168
   Abstract »    Full Text »    PDF »
Nuclear Heat Shock Protein 72 as a Negative Regulator of Oxidative Stress (Hydrogen Peroxide)-Induced HMGB1 Cytoplasmic Translocation and Release.
D. Tang, R. Kang, W. Xiao, L. Jiang, M. Liu, Y. Shi, K. Wang, H. Wang, and X. Xiao (2007)
J. Immunol. 178, 7376-7384
   Abstract »    Full Text »    PDF »
Cardiac mitochondrial bioenergetics, oxidative stress, and aging.
S. Judge and C. Leeuwenburgh (2007)
Am J Physiol Cell Physiol 292, C1983-C1992
   Abstract »    Full Text »    PDF »
Expression of catalytic mutants of the mtDNA helicase Twinkle and polymerase POLG causes distinct replication stalling phenotypes.
S. Wanrooij, S. Goffart, J. L.O. Pohjoismaki, T. Yasukawa, and J. N. Spelbrink (2007)
Nucleic Acids Res. 35, 3238-3251
   Abstract »    Full Text »    PDF »
Oxidative Stress, Mitochondrial DNA Mutation, and Apoptosis in Aging.
H.-C. Lee and Y.-H. Wei (2007)
Experimental Biology and Medicine 232, 592-606
   Abstract »    Full Text »    PDF »
Highly Tolerated Amino Acid Substitutions Increase the Fidelity of Escherichia coli DNA Polymerase I.
E. Loh, J. Choe, and L. A. Loeb (2007)
J. Biol. Chem. 282, 12201-12209
   Abstract »    Full Text »    PDF »
Mitochondrial Dysfunction in Atherosclerosis.
N. R. Madamanchi and M. S. Runge (2007)
Circ. Res. 100, 460-473
   Abstract »    Full Text »    PDF »
Accumulation of Mitochondrial DNA Deletion Mutations in Aged Muscle Fibers: Evidence for a Causal Role in Muscle Fiber Loss.
A. Herbst, J. W. Pak, D. McKenzie, E. Bua, M. Bassiouni, and J. M. Aiken (2007)
J. Gerontol. A Biol. Sci. Med. Sci. 62, 235-245
   Abstract »    Full Text »    PDF »
Knockdown of Mitochondrial Heat Shock Protein 70 Promotes Progeria-like Phenotypes in Caenorhabditis elegans.
K. Kimura, N. Tanaka, N. Nakamura, S. Takano, and S. Ohkuma (2007)
J. Biol. Chem. 282, 5910-5918
   Abstract »    Full Text »    PDF »
Amelioration of progressive renal injury by genetic manipulation of Klotho gene.
Y. Haruna, N. Kashihara, M. Satoh, N. Tomita, T. Namikoshi, T. Sasaki, T. Fujimori, P. Xie, and Y. S. Kanwar (2007)
PNAS 104, 2331-2336
   Abstract »    Full Text »    PDF »
Age-dependent accumulation of mtDNA mutations in murine hematopoietic stem cells is modulated by the nuclear genetic background.
Y.-G. Yao, F. M. Ellison, J. P. McCoy, J. Chen, and N. S. Young (2007)
Hum. Mol. Genet. 16, 286-294
   Abstract »    Full Text »    PDF »
Cell and animal models of mtDNA biology: progress and prospects.
S. M. Khan, R. M. Smigrodzki, and R. H. Swerdlow (2007)
Am J Physiol Cell Physiol 292, C658-C669
   Abstract »    Full Text »    PDF »
Vascular Cell Senescence: Contribution to Atherosclerosis.
T. Minamino and I. Komuro (2007)
Circ. Res. 100, 15-26
   Abstract »    Full Text »    PDF »
Mitochondrial Targeting with Antioxidant Peptide SS-31 Prevents Mitochondrial Depolarization, Reduces Islet Cell Apoptosis, Increases Islet Cell Yield, and Improves Posttransplantation Function.
D. A. Thomas, C. Stauffer, K. Zhao, H. Yang, V. K. Sharma, H. H. Szeto, and M. Suthanthiran (2007)
J. Am. Soc. Nephrol. 18, 213-222
   Abstract »    Full Text »    PDF »
Incorporation and Replication of 8-Oxo-deoxyguanosine by the Human Mitochondrial DNA Polymerase.
J. W. Hanes, D. M. Thal, and K. A. Johnson (2006)
J. Biol. Chem. 281, 36241-36248
   Abstract »    Full Text »    PDF »
Abnormal Ca2+ Dynamics in Transgenic Mice with Neuron-Specific Mitochondrial DNA Defects..
M. Kubota, T. Kasahara, T. Nakamura, M. Ishiwata, T. Miyauchi, and T. Kato (2006)
J. Neurosci. 26, 12314-12324
   Abstract »    Full Text »    PDF »
Increased Apoptosis in Cystinotic Fibroblasts and Renal Proximal Tubule Epithelial Cells Results from Cysteinylation of Protein Kinase C{delta}.
M. A. Park, V. Pejovic, K. G. Kerisit, S. Junius, and J. G. Thoene (2006)
J. Am. Soc. Nephrol. 17, 3167-3175
   Abstract »    Full Text »    PDF »
Molecular bases of progeroid syndromes.
C. L. Navarro, P. Cau, and N. Levy (2006)
Hum. Mol. Genet. 15, R151-R161
   Abstract »    Full Text »    PDF »
Mitochondrial DNA polymerase-{gamma} and human disease.
G. Hudson and P. F. Chinnery (2006)
Hum. Mol. Genet. 15, R244-R252
   Abstract »    Full Text »    PDF »
Serum Peptidome Patterns That Distinguish Metastatic Thyroid Carcinoma from Cancer-free Controls Are Unbiased by Gender and Age.
J. Villanueva, A. J. Martorella, K. Lawlor, J. Philip, M. Fleisher, R. J. Robbins, and P. Tempst (2006)
Mol. Cell. Proteomics 5, 1840-1852
   Abstract »    Full Text »    PDF »
Acetylation of Mouse p53 at Lysine 317 Negatively Regulates p53 Apoptotic Activities after DNA Damage..
C. Chao, Z. Wu, S. J. Mazur, H. Borges, M. Rossi, T. Lin, J. Y. J. Wang, C. W. Anderson, E. Appella, and Y. Xu (2006)
Mol. Cell. Biol. 26, 6859-6869
   Abstract »    Full Text »    PDF »
Mitochondrial DNA mutations and apoptosis in Mammalian aging..
G. C. Kujoth, C. Leeuwenburgh, and T. A. Prolla (2006)
Cancer Res. 66, 7386-7389
   Abstract »    Full Text »    PDF »
Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock.
R. V. Kondratov, A. A. Kondratova, V. Y. Gorbacheva, O. V. Vykhovanets, and M. P. Antoch (2006)
Genes & Dev. 20, 1868-1873
   Abstract »    Full Text »    PDF »
Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span..
N. D. Bonawitz, M. S. Rodeheffer, and G. S. Shadel (2006)
Mol. Cell. Biol. 26, 4818-4829
   Abstract »    Full Text »    PDF »
DNA precursor metabolism and genomic stability.
C. K. Mathews (2006)
FASEB J 20, 1300-1314
   Abstract »    Full Text »    PDF »
Apoptosis in mitochondrial myopathies is linked to mitochondrial proliferation.
K. Aure, G. Fayet, J. P. Leroy, E. Lacene, N. B. Romero, and A. Lombes (2006)
Brain 129, 1249-1259
   Abstract »    Full Text »    PDF »
Reactive Oxygen Species-Mediated Mitochondria-to-Nucleus Signaling: A Key to Aging and Radical-Caused Diseases.
P. Storz (2006)
Sci. STKE 2006, re3
   Abstract »    Full Text »    PDF »
The p53 Pathway Promotes Efficient Mitochondrial DNA Base Excision Repair in Colorectal Cancer Cells..
D. Chen, Z. Yu, Z. Zhu, and C. D. Lopez (2006)
Cancer Res. 66, 3485-3494
   Abstract »    Full Text »    PDF »
Therapeutic Approach for Diabetic Nephropathy Using Gene Delivery of Translocase of Inner Mitochondrial Membrane 44 by Reducing Mitochondrial Superoxide Production.
Y. Zhang, J. Wada, I. Hashimoto, J. Eguchi, A. Yasuhara, Y. S. Kanwar, K. Shikata, and H. Makino (2006)
J. Am. Soc. Nephrol. 17, 1090-1101
   Abstract »    Full Text »    PDF »
Functional Human Mitochondrial DNA Polymerase {gamma} Forms a Heterotrimer.
E. Yakubovskaya, Z. Chen, J. A. Carrodeguas, C. Kisker, and D. F. Bogenhagen (2006)
J. Biol. Chem. 281, 374-382
   Abstract »    Full Text »    PDF »
Nuclear-Mitochondrial Epistasis and Drosophila Aging: Introgression of Drosophila simulans mtDNA Modifies Longevity in D. melanogaster Nuclear Backgrounds.
D. M. Rand, A. Fry, and L. Sheldahl (2006)
Genetics 172, 329-341
   Abstract »    Full Text »    PDF »
Age-related changes in cardiac structure and function in Fischer 344 x Brown Norway hybrid rats.
T. A. Hacker, S. H. McKiernan, P. S. Douglas, J. Wanagat, and J. M. Aiken (2006)
Am J Physiol Heart Circ Physiol 290, H304-H311
   Abstract »    Full Text »    PDF »
The mitochondrial theory of aging and its relationship to reactive oxygen species damage and somatic mtDNA mutations.
L. A. Loeb, D. C. Wallace, and G. M. Martin (2005)
PNAS 102, 18769-18770
   Full Text »    PDF »
From the Cover: Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production.
A. Trifunovic, A. Hansson, A. Wredenberg, A. T. Rovio, E. Dufour, I. Khvorostov, J. N. Spelbrink, R. Wibom, H. T. Jacobs, and N.-G. Larsson (2005)
PNAS 102, 17993-17998
   Abstract »    Full Text »    PDF »
Highlights from the Literature.
(2005)
Physiology 20, 369-373
   Full Text »    PDF »
Mitochondrial Dynamics in Cell Life and Death.
C. Scheckhuber (2005)
Sci. Aging Knowl. Environ. 2005, pe36
   Abstract »    Full Text »
Mitochondrial Genetics of Aging: Intergenomic Conflict Resolution.
D. M. Rand (2005)
Sci. Aging Knowl. Environ. 2005, re5
   Abstract »    Full Text »    PDF »
Developing a Research Agenda in Biogerontology: Basic Mechanisms.
H. R. Warner (2005)
Sci. Aging Knowl. Environ. 2005, pe33
   Abstract »    Full Text »
Error Prone.
R. J. Davenport (2005)
Sci. Aging Knowl. Environ. 2005, nf57
   Abstract »    Full Text »


ADVERTISEMENT
Click Me!

ADVERTISEMENT
Click Me!

To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)