The role of mitochondrial DNA mutations and free radicals in disease and ageing

Abstract

Considerable efforts have been made to understand the role of oxidative stress in age‐related diseases and ageing. The mitochondrial free radical theory of ageing, which proposes that damage to mitochondrial DNA (mt DNA ) and other macromolecules caused by the production of reactive oxygen species ( ROS ) during cellular respiration drives ageing, has for a long time been the central hypothesis in the field. However, in contrast with this theory, evidence from an increasing number of experimental studies has suggested that mt DNA mutations may be generated by replication errors rather than by accumulated oxidative damage. Furthermore, interventions to modulate ROS levels in humans and animal models have not produced consistent results in terms of delaying disease progression and extending lifespan. A number of recent experimental findings strongly question the mitochondrial free radical theory of ageing, leading to the emergence of new theories of how age‐associated mitochondrial dysfunction may lead to ageing. These new hypotheses are mainly based on the underlying notion that, despite their deleterious role, ROS are essential signalling molecules that mediate stress responses in general and the stress response to age‐dependent damage in particular. This novel view of ROS roles has a clear impact on the interpretation of studies in which antioxidants have been used to treat human age‐related diseases commonly linked to oxidative stress.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 109

1. 1.

   Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298-300.

   Not in our library10.1093/geronj/11.3.298

2. 2.

   McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969;244:6049-55.

   Not in our library

3. 3.

   Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972;20:145-7.

   Not in our library10.1111/j.1532-5415.1972.tb00787.x

4. 4.

   Miquel J, Economos AC, Fleming J, Johnson JE. Mitochondrial role in cell aging. Exp Gerontol. 1980;15:575-91.

   Not in our library10.1016/0531-5565(80)90010-8

5. 5.

   Kelly DP. Cell biology: ageing theories unified. Nature. 2011;470:342-3.

   Not in our library10.1038/nature09896

6. 6.

   Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell. 2012;48:158-67.

   Not in our library10.1016/j.molcel.2012.09.025

7. 7.

   Hekimi S, Lapointe J, Wen Y. Taking a “good” look at free radicals in the aging process. Trends Cell Biol. 2011;21:569-76.

   Not in our library10.1016/j.tcb.2011.06.008

8. 8.

   Larsson NG, Clayton DA. Molecular genetic aspects of human mitochondrial disorders. Annu Rev Genet. 1995;29:151-78.

   Not in our library10.1146/annurev.ge.29.120195.001055

9. 9.

   Bogenhagen D, Clayton DA. Mouse L cell mitochondrial DNA molecules are selected randomly for replication throughout the cell cycle. Cell. 1977;11:719-27.

   Not in our library10.1016/0092-8674(77)90286-0

10. 10.

    Trifunovic A, Larsson NG. Mitochondrial dysfunction as a cause of ageing. J Intern Med. 2008;263:167-78.

    Not in our library10.1111/j.1365-2796.2007.01905.x

11. 11.

    Jenuth JP, Peterson AC, Shoubridge EA. Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat Genet. 1997;16:93-5.

    Not in our library10.1038/ng0597-93

12. 12.

    Wallace DC. Mitochondrial diseases in man and mouse. Science. 1999;283:1482-8.

    Not in our library10.1126/science.283.5407.1482

13. 13.

    Dufour E, Terzioglu M, Sterky FH, et al. Age-associated mosaic respiratory chain deficiency causes trans-neuronal degeneration. Hum Mol Genet. 2008;17:1418-26.

    Not in our library10.1093/hmg/ddn030

14. 14.

    Larsson NG. Somatic mitochondrial DNA mutations in mammalian aging. Annu Rev Biochem. 2010;79:683-706.

    Not in our library10.1146/annurev-biochem-060408-093701

15. 15.

    Kukat C, Wurm CA, Spahr H, Falkenberg M, Larsson NG, Jakobs S. Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. Proc Natl Acad Sci U S A. 2011;108:13534-9.

    Not in our library10.1073/pnas.1109263108

16. 16.

    Bogenhagen DF, Pinz KG, Perez-Jannotti RM. Enzymology of mitochondrial base excision repair. Prog Nucleic Acid Res Mol Biol. 2001;68:257-71.

    Not in our library10.1016/s0079-6603(01)68105-4

17. 17.

    Boesch P, Weber-Lotfi F, Ibrahim N, et al. DNA repair in organelles: pathways, organization, regulation, relevance in disease and aging. Biochim Biophys Acta. 2011;1813:186-200.

    Not in our library10.1016/j.bbamcr.2010.10.002

18. 18.

    Szczesny B, Hazra TK, Papaconstantinou J, Mitra S, Boldogh I. Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases. Proc Natl Acad Sci U S A. 2003;100:10670-5.

    Not in our library10.1073/pnas.1932854100

19. 19.
    Ultra-Deep Sequencing of Mouse Mitochondrial DNA: Mutational Patterns and Their Origins · 2011

    No notice
20. 20.

    Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429:417-23.

    Not in our library10.1038/nature02517

21. 21.

    Kujoth GC, Hiona A, Pugh TD, et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005;309:481-4.

    Not in our library10.1126/science.1112125

22. 22.

    Ahlqvist KJ, Hamalainen RH, Yatsuga S, et al. Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in polg mutator mice. Cell Metab. 2012;15:100-9.

    Not in our library10.1016/j.cmet.2011.11.012

23. 23.

    Tyynismaa H, Mjosund KP, Wanrooij S, et al. Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice. Proc Natl Acad Sci U S A. 2005;102:17687-92.

    Not in our library10.1073/pnas.0505551102

24. 24.

    Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120:483-95.

    Not in our library10.1016/j.cell.2005.02.001

25. 25.

    Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature. 1961;191:144-8.

    Not in our library10.1038/191144a0

26. 26.

    Rigoulet M, Yoboue ED, Devin A. Mitochondrial ROS generation and its regulation: mechanisms involved in H(2)O(2) signaling. Antioxid Redox Signal. 2011;14:459-68.

    Not in our library10.1089/ars.2010.3363

27. 27.

    Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1-13.

    Not in our library10.1042/bj20081386

28. 28.

    Brookes PS. Mitochondrial H(+) leak and ROS generation: an odd couple. Free Radic Biol Med. 2005;38:12-23.

    Not in our library10.1016/j.freeradbiomed.2004.10.016

29. 29.

    Murphy MP, Holmgren A, Larsson NG, et al. Unraveling the biological roles of reactive oxygen species. Cell Metab. 2011;13:361-6.

    Not in our library10.1016/j.cmet.2011.03.010

30. 30.

    Alexeyev MF. Is there more to aging than mitochondrial DNA and reactive oxygen species? FEBS J. 2009;276:5768-87.

    Not in our library10.1111/j.1742-4658.2009.07269.x

31. 31.

    Wardman P. Fluorescent and luminescent probes for measurement of oxidative and nitrosative species in cells and tissues: progress, pitfalls, and prospects. Free Radic Biol Med. 2007;43:995-1022.

    Not in our library10.1016/j.freeradbiomed.2007.06.026

32. 32.

    Zielonka J, Kalyanaraman B. Hydroethidine- and MitoSOX-derived red fluorescence is not a reliable indicator of intracellular superoxide formation: another inconvenient truth. Free Radic Biol Med. 2010;48:983-1001.

    Not in our library10.1016/j.freeradbiomed.2010.01.028

33. 33.

    Votyakova TV, Reynolds IJ. Detection of hydrogen peroxide with Amplex Red: interference by NADH and reduced glutathione auto-oxidation. Arch Biochem Biophys. 2004;431:138-44.

    Not in our library10.1016/j.abb.2004.07.025

34. 34.

    Hanson GT, Aggeler R, Oglesbee D, et al. Investigating mitochondrial redox potential with redox-sensitive green fluorescent protein indicators. J Biol Chem. 2004;279:13044-53.

    Not in our library10.1074/jbc.m312846200

35. 35.

    Belousov VV, Fradkov AF, Lukyanov KA, et al. Genetically encoded fluorescent indicator for intracellular hydrogen peroxide. Nat Methods. 2006;3:281-6.

    Not in our library10.1038/nmeth866

36. 36.

    Rhee SG, Chang TS, Jeong W, Kang D. Methods for detection and measurement of hydrogen peroxide inside and outside of cells. Mol Cells. 2010;29:539-49.

    Not in our library10.1007/s10059-010-0082-3

37. 37.

    Albrecht SC, Barata AG, Grosshans J, Teleman AA, Dick TP. In vivo mapping of hydrogen peroxide and oxidized glutathione reveals chemical and regional specificity of redox homeostasis. Cell Metab. 2011;14:819-29.

    Not in our library10.1016/j.cmet.2011.10.010

38. 38.
    Measurement of H2O2 within Living Drosophila during Aging Using a Ratiometric Mass Spectrometry Probe Targeted to the Mitochondrial Matrix · 2011

    No notice
39. 39.

    Schriner SE, Linford NJ, Martin GM, et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005;308:1909-11.

    Not in our library10.1126/science.1106653

40. 40.

    Kirby K, Hu J, Hilliker AJ, Phillips JP. RNA interference-mediated silencing of Sod2 in Drosophila leads to early adult-onset mortality and elevated endogenous oxidative stress. Proc Natl Acad Sci U S A. 2002;99:16162-7.

    Not in our library10.1073/pnas.252342899

Cited by papers we hold 8

• Mitochondrial dysfunction: roles in skeletal muscle atrophy · 2023
  No notice
• Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives · 2022
  No notice
• The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer · 2022
  No notice
• Selenium-Dependent Antioxidant Enzymes: Actions and Properties of Selenoproteins · 2018
  No notice
• Impact of Aging and Exercise on Mitochondrial Quality Control in Skeletal Muscle · 2017
  No notice
• ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age‐Related Diseases · 2016
  No notice
• Protein biogenesis machinery is a driver of replicative aging in yeast · 2015
  No notice
• Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health · 2014
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.