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Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice

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Abstract

An increase in mitochondrial DNA (mtDNA) mutations and an ensuing increase in mitochondrial reactive oxygen species (ROS) production have been suggested to be a cause of the aging process (“the mitochondrial hypothesis of aging”). In agreement with this, mtDNA-mutator mice accumulate a large amount of mtDNA mutations, giving rise to defective mitochondria and an accelerated aging phenotype. However, incongruously, the rates of ROS production in mtDNA mutator mitochondria have generally earlier been reported to be lower – not higher – than in wildtype, thus apparently invalidating the “mitochondrial hypothesis of aging”. We have here re-examined ROS production rates in mtDNA-mutator mice mitochondria. Using traditional conditions for measuring ROS (succinate in the absence of rotenone), we indeed found lower ROS in the mtDNA-mutator mitochondria compared to wildtype. This ROS mainly results from reverse electron flow driven by the membrane potential, but the membrane potential reached in the isolated mtDNA-mutator mitochondria was 33 mV lower than that in wildtype mitochondria, due to the feedback inhibition of succinate oxidation by oxaloacetate, and to a lower oxidative capacity in the mtDNA-mutator mice, explaining the lower ROS production. In contrast, in normal forward electron flow systems (pyruvate (or glutamate) + malate or palmitoyl-CoA + carnitine), mitochondrial ROS production was higher in the mtDNA-mutator mitochondria. Particularly, even during active oxidative phosphorylation (as would be ongoing physiologically), higher ROS rates were seen in the mtDNA-mutator mitochondria than in wildtype. Thus, when examined under physiological conditions, mitochondrial ROS production rates are indeed increased in mtDNA-mutator mitochondria. While this does not prove the validity of the mitochondrial hypothesis of aging, it may no longer be said to be negated in this respect. This paper is dedicated to the memory of Professor Vladimir P. Skulachev.

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Abbreviations

mtDNA:

mitochondrial DNA

ROS:

reactive oxygen species

References

  1. Sanchez-Contreras, M., and Kennedy, S. R. (2022) The complicated nature of somatic mtDNA mutations in aging, Front. Aging, 2, 805126, https://doi.org/10.3389/fragi.2021.805126.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Harman, D. (2003) The free radical theory of aging, Antioxid. Redox Signal., 5, 557-561, https://doi.org/10.1089/152308603770310202.

    Article  CAS  PubMed  Google Scholar 

  3. Skulachev, V. P., and Lyamzaev, K. G. (2021) Mitochondrial Reactive Oxygen Species Aging Theory, in Encyclopedia of Gerontology and Population Aging (Gu, D., and Dupre, M. E., eds) Springer International Publishing, Cham, 2021, pp. 3249-3256, https://doi.org/10.1007/978-3-030-22009-9_47.

  4. Salmon, A. B., Richardson, A., and Perez, V. I. (2010) Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging? Free Radic. Biol. Med., 48, 642-655, https://doi.org/10.1016/j.freeradbiomed.2009.12.015.

    Article  CAS  PubMed  Google Scholar 

  5. Lagouge, M., and Larsson, N. G. (2013) The role of mitochondrial DNA mutations and free radicals in disease and ageing, J. Intern. Med., 273, 529-543, https://doi.org/10.1111/joim.12055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Brand, M. D. (2020) Riding the tiger – physiological and pathological effects of superoxide and hydrogen peroxide generated in the mitochondrial matrix, Crit. Rev. Biochem. Mol. Biol., 55, 592-661, https://doi.org/10.1080/10409238.2020.1828258.

    Article  CAS  PubMed  Google Scholar 

  7. Edgar, D., and Trifunovic, A. (2009) The mtDNA mutator mouse: Dissecting mitochondrial involvement in aging, Aging (Albany NY), 1, 1028-1032, https://doi.org/10.18632/aging.100109.

    Article  CAS  PubMed  Google Scholar 

  8. Larsson, N. G. (2010) Somatic mitochondrial DNA mutations in mammalian aging, Annu. Rev. Biochem., 79, 683-706, https://doi.org/10.1146/annurev-biochem-060408-093701.

    Article  CAS  PubMed  Google Scholar 

  9. Capel, F., Rimbert, V., Lioger, D., Diot, A., Rousset, P., Mirand, P. P., Boirie, Y., Morio, B., and Mosoni, L. (2005) Due to reverse electron transfer, mitochondrial H2O2 release increases with age in human vastus lateralis muscle although oxidative capacity is preserved, Mech. Ageing Dev., 126, 505-511, https://doi.org/10.1016/j.mad.2004.11.001.

    Article  CAS  PubMed  Google Scholar 

  10. Sohal, R. S., Arnold, L. A., and Sohal, B. H. (1990) Age-related changes in antioxidant enzymes and prooxidant generation in tissues of the rat with special reference to parameters in two insect species, Free Radic. Biol. Med., 9, 495-500, https://doi.org/10.1016/0891-5849(90)90127-5.

    Article  CAS  PubMed  Google Scholar 

  11. Lass, A., Sohal, B. H., Weindruch, R., Forster, M. J., and Sohal, R. S. (1998) Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria, Free Radic. Biol. Med., 25, 1089-1097, https://doi.org/10.1016/S0891-5849(98)00144-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mansouri, A., Muller, F. L., Liu, Y., Ng, R., Faulkner, J., Hamilton, M., Richardson, A., Huang, T. T., Epstein, C. J., and Van Remmen, H. (2006) Alterations in mitochondrial function, hydrogen peroxide release and oxidative damage in mouse hind-limb skeletal muscle during aging, Mech. Ageing Dev., 127, 298-306, https://doi.org/10.1016/j.mad.2005.11.004.

    Article  CAS  PubMed  Google Scholar 

  13. Chabi, B., Ljubicic, V., Menzies, K. J., Huang, J. H., Saleem, A., and Hood, D. A. (2008) Mitochondrial function and apoptotic susceptibility in aging skeletal muscle, Aging Cell, 7, 2-12, https://doi.org/10.1111/j.1474-9726.2007.00347.x.

    Article  CAS  PubMed  Google Scholar 

  14. Hansford, R. G., Hogue, B. A., and Mildaziene, V. (1997) Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age, J. Bioenerg. Biomembr., 29, 89-95, https://doi.org/10.1023/A:1022420007908.

    Article  CAS  PubMed  Google Scholar 

  15. Drew, B., Phaneuf, S., Dirks, A., Selman, C., Gredilla, R., Lezza, A., Barja, G., and Leeuwenburgh, C. (2003) Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart, Am. J. Physiol. Regul. Integr. Comp. Physiol., 284, R474-R480, https://doi.org/10.1152/ajpregu.00455.2002.

    Article  CAS  PubMed  Google Scholar 

  16. Simmons, R. A., Suponitsky-Kroyter, I., and Selak, M. A. (2005) Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to beta-cell failure, J. Biol. Chem., 280, 28785-28791, https://doi.org/10.1074/jbc.M505695200.

    Article  CAS  PubMed  Google Scholar 

  17. Papa, S., Sardanelli, A. M., Capitanio, N., and Piccoli, C. (2009) Mitochondrial respiratory dysfunction and mutations in mitochondrial DNA in PINK1 familial parkinsonism, J. Bioenerg. Biomemb., 41, 509-516, https://doi.org/10.1007/s10863-009-9252-4.

    Article  CAS  Google Scholar 

  18. Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly, Y. M., Gidlof, S., Oldfors, A., Wibom, R., Tornell, J., Jacobs, H. T., and Larsson, N. G. (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase, Nature, 429, 417-423, https://doi.org/10.1038/nature02517.

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Kujoth, G. C., Hiona, A., Pugh, T. D., Someya, S., Panzer, K., Wohlgemuth, S. E., Hofer, T., Seo, A. Y., Sullivan, R., Jobling, W. A., Morrow, J. D., Van Remmen, H., Sedivy, J. M., Yamasoba, T., Tanokura, M., Weindruch, R., Leeuwenburgh, C., and Prolla, T. A. (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging, Science, 309, 481-484, https://doi.org/10.1126/science.1112125.

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Trifunovic, A., Hansson, A., Wredenberg, A., Rovio, A. T., Dufour, E., Khvorostov, I., Spelbrink, J. N., Wibom, R., Jacobs, H. T., and Larsson, N. G. (2005) Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production, Proc. Natl. Acad. Sci. USA, 102, 17993-17998, https://doi.org/10.1073/pnas.0508886102.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kolesar, J. E., Safdar, A., Abadi, A., MacNeil, L. G., Crane, J. D., Tarnopolsky, M. A., and Kaufman, B. A. (2014) Defects in mitochondrial DNA replication and oxidative damage in muscle of mtDNA mutator mice, Free Radic. Biol. Med., 75, 241-251, https://doi.org/10.1016/j.freeradbiomed.2014.07.038.

    Article  CAS  PubMed  Google Scholar 

  22. Yu, T., Slone, J., Liu, W., Barnes, R., Opresko, P. L., Wark, L., Mai, S., Horvath, S., and Huang, T. (2022) Premature aging is associated with higher levels of 8-oxoguanine and increased DNA damage in the Polg mutator mouse, Aging Cell, 21, e13669, https://doi.org/10.1111/acel.13669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kukat, A., Dogan, S. A., Edgar, D., Mourier, A., Jacoby, C., Maiti, P., Mauer, J., Becker, C., Senft, K., Wibom, R., Kudin, A. P., Hultenby, K., Flogel, U., Rosenkranz, S., Ricquier, D., Kunz, W. S., and Trifunovic, A. (2014) Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity, PLoS Genet., 10, e1004385, https://doi.org/10.1371/journal.pgen.1004385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hiona, A., Sanz, A., Kujoth, G. C., Pamplona, R., Seo, A. Y., Hofer, T., Someya, S., Miyakawa, T., Nakayama, C., Samhan-Arias, A. K., Servais, S., Barger, J. L., Portero-Otin, M., Tanokura, M., Prolla, T. A., and Leeuwenburgh, C. (2010) Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice, PLoS One, 5, e11468, https://doi.org/10.1371/journal.pone.0011468.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  25. Logan, A., Shabalina, I. G., Prime, T. A., Rogatti, S., Kalinovich, A. V., Hartley, R. C., Budd, R. C., Cannon, B., and Murphy, M. P. (2014) In vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator mice, Aging Cell, 13, 765-768, https://doi.org/10.1111/acel.12212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shabalina, I. G., Vyssokikh, M. Y., Gibanova, N., Csikasz, R. I., Edgar, D., Hallden-Waldemarson, A., Rozhdestvenskaya, Z., Bakeeva, L. E., Vays, V. B., Pustovidko, A. V., Skulachev, M. V., Cannon, B., Skulachev, V. P., and Nedergaard, J. (2017) Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1, Aging, 9, 315-339, https://doi.org/10.18632/aging.101174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dai, D. F., Chen, T., Wanagat, J., Laflamme, M., Marcinek, D. J., Emond, M. J., Ngo, C. P., Prolla, T. A., and Rabinovitch, P. S. (2010) Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria, Aging Cell, 9, 536-544, https://doi.org/10.1111/j.1474-9726.2010.00581.x.

    Article  CAS  PubMed  Google Scholar 

  28. Edgar, D., Shabalina, I., Camara, Y., Wredenberg, A., Calvaruso, M. A., Nijtmans, L., Nedergaard, J., Cannon, B., Larsson, N. G., and Trifunovic, A. (2009) Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice, Cell Metab., 10, 131-138, https://doi.org/10.1016/j.cmet.2009.06.010.

    Article  CAS  PubMed  Google Scholar 

  29. Silva, J. P., Shabalina, I. G., Dufour, E., Petrovic, N., Backlund, E. C., Hultenby, K., Wibom, R., Nedergaard, J., Cannon, B., and Larsson, N. G. (2005) SOD2 overexpression: enhanced mitochondrial tolerance but absence of effect on UCP activity, EMBO J., 24, 4061-4070, https://doi.org/10.1038/sj.emboj.7600866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Udenfriend, S., Stein, S., Bohlen, P., Dairman, W., Leimgruber, W., and Weigele, M. (1972) Fluorescamine: a reagent for assay of amino acids, peptides, proteins, and primary amines in the picomole range, Science, 178, 871-872, https://doi.org/10.1126/science.178.4063.871.

    Article  ADS  CAS  PubMed  Google Scholar 

  31. Kettle, A. J., Carr, A. C., and Winterbourn, C. C. (1994) Assays using horseradish peroxidase and phenolic substrates require superoxide dismutase for accurate determination of hydrogen peroxide production by neutrophils, Free Radic. Biol. Med., 17, 161-164, https://doi.org/10.1016/0891-5849(94)90111-2.

    Article  CAS  PubMed  Google Scholar 

  32. Shabalina, I. G., Vrbacky, M., Pecinova, A., Kalinovich, A. V., Drahota, Z., Houstek, J., Mracek, T., Cannon, B., and Nedergaard, J. (2014) ROS production in brown adipose tissue mitochondria: The question of UCP1-dependence, Biochim. Biophys. Acta, 1837, 2017-2030, https://doi.org/10.1016/j.bbabio.2014.04.005.

    Article  CAS  PubMed  Google Scholar 

  33. Salvi, M., Battaglia, V., Brunati, A. M., La Rocca, N., Tibaldi, E., Pietrangeli, P., Marcocci, L., Mondovi, B., Rossi, C. A., and Toninello, A. (2007) Catalase takes part in rat liver mitochondria oxidative stress defense, J. Biol. Chem., 282, 24407-24415, https://doi.org/10.1074/jbc.M701589200.

    Article  CAS  PubMed  Google Scholar 

  34. Panov, A., Dikalov, S., Shalbuyeva, N., Hemendinger, R., Greenamyre, J. T., and Rosenfeld, J. (2007) Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice, Am. J. Physiol. Cell Physiol., 292, C708-C718, https://doi.org/10.1152/ajpcell.00202.2006.

    Article  CAS  PubMed  Google Scholar 

  35. Shabalina, I. G., Hoeks, J., Kramarova, T. V., Schrauwen, P., Cannon, B., and Nedergaard, J. (2010) Cold tolerance of UCP1-ablated mice: A skeletal muscle mitochondria switch toward lipid oxidation with marked UCP3 up-regulation not associated with increased basal, fatty acid- or ROS-induced uncoupling or enhanced GDP effects, Biochim. Biophys. Acta, 1797, 968-980, https://doi.org/10.1016/j.bbabio.2010.02.033.

    Article  CAS  PubMed  Google Scholar 

  36. Nedergaard, J. (1983) The relationship between extramitochondrial Ca2+ concentration, respiratory rate, and membrane potential in mitochondria from brown adipose tissue of the rat, Eur. J. Biochem., 133, 185-191, https://doi.org/10.1111/j.1432-1033.1983.tb07446.x.

    Article  CAS  PubMed  Google Scholar 

  37. Sahlin, K., Shabalina, I. G., Mattsson, C. M., Bakkman, L., Fernstrom, M., Rozhdestvenskaya, Z., Enqvist, J. K., Nedergaard, J., Ekblom, B., and Tonkonogi, M. (2010) Ultraendurance exercise increases the production of reactive oxygen species in isolated mitochondria from human skeletal muscle, J. Appl. Physiol., 108, 780-787, https://doi.org/10.1152/japplphysiol.00966.2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shabalina, I. G., Petrovic, N., Kramarova, T. V., Hoeks, J., Cannon, B., and Nedergaard, J. (2006) UCP1 and defense against oxidative stress. 4-Hydroxy-2-nonenal effects on brown fat mitochondria are uncoupling protein 1-independent, J. Biol. Chem., 281, 13882-13893, https://doi.org/10.1074/jbc.M601387200.

    Article  CAS  PubMed  Google Scholar 

  39. Skulachev, V. P. (1996) Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants, Q. Rev. Biophys., 29, 169-202, https://doi.org/10.1017/S0033583500005795.

    Article  CAS  PubMed  Google Scholar 

  40. Murphy, M. P. (2009) How mitochondria produce reactive oxygen species, Biochem. J., 417, 1-13, https://doi.org/10.1042/BJ20081386.

    Article  CAS  PubMed  Google Scholar 

  41. Brand, M. D. (2010) The sites and topology of mitochondrial superoxide production, Exp. Gerontol., 45, 466-472, https://doi.org/10.1016/j.exger.2010.01.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lambert, A. J., Boysen, H. M., Buckingham, J. A., Yang, T., Podlutsky, A., Austad, S. N., Kunz, T. H., Buffenstein, R., and Brand, M. D. (2007) Low rates of hydrogen peroxide production by isolated heart mitochondria associate with long maximum lifespan in vertebrate homeotherms, Aging Cell, 6, 607-618, https://doi.org/10.1111/j.1474-9726.2007.00312.x.

    Article  CAS  PubMed  Google Scholar 

  43. Scialo, F., Sriram, A., Fernandez-Ayala, D., Gubina, N., Lohmus, M., Nelson, G., Logan, A., Cooper, H. M., Navas, P., Enriquez, J. A., Murphy, M. P., and Sanz, A. (2016) Mitochondrial ROS produced via reverse electron transport extend animal lifespan, Cell Metab., 23, 725-734, https://doi.org/10.1016/j.cmet.2016.03.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Brand, M. D., Goncalves, R. L. S., Orr, A. L., Vargas, L., Gerencser, A. A., Borch Jensen, M., Wang, Y. T., Melov, S., Turk, C. N., Matzen, J. T., Dardov, V. J., Petrassi, H. M., Meeusen, S. L., Perevoshchikova, I. V., Jasper, H., Brookes, P. S., and Ainscow, E. K. (2016) Suppressors of superoxide-H2O2 production at site IQ of mitochondrial complex I protect against stem cell hyperplasia and ischemia-reperfusion injury, Cell Metab., 24, 582-592, https://doi.org/10.1016/j.cmet.2016.08.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Goncalves, R. L. S., Quinlan, C. L., Perevoshchikova, I. V., Hey-Mogensen, M., and Brand, M. D. (2015) Sites of superoxide and hydrogen peroxide production by muscle mitochondria assessed ex vivo under conditions mimicking rest and exercise, J. Biol. Chem., 290, 209-227, https://doi.org/10.1074/jbc.M114.619072.

    Article  CAS  PubMed  Google Scholar 

  46. Fendel, U., Tocilescu, M. A., Kerscher, S., and Brandt, U. (2008) Exploring the inhibitor binding pocket of respiratory complex I, Biochim. Biophys. Acta, 1777, 660-665, https://doi.org/10.1016/j.bbabio.2008.04.033.

    Article  CAS  PubMed  Google Scholar 

  47. Boveris, A., and Chance, B. (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen, Biochem. J., 134, 707-716, https://doi.org/10.1042/bj1340707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Korshunov, S. S., Skulachev, V. P., and Starkov, A. A. (1997) High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria, FEBS Lett., 416, 15-18, https://doi.org/10.1016/S0014-5793(97)01159-9.

    Article  CAS  PubMed  Google Scholar 

  49. Fink, B. D., Bai, F., Yu, L., Sheldon, R. D., Sharma, A., Taylor, E. B., and Sivitz, W. I. (2018) Oxaloacetic acid mediates ADP-dependent inhibition of mitochondrial complex II-driven respiration, J. Biol. Chem., 293, 19932-19941, https://doi.org/10.1074/jbc.RA118.005144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zeyelmaker, W. P., and Slater, E. C. (1967) The inhibition of succinate dehydrogenase by oxaloacetate, Biochim. Biophys. Acta, 132, 210-212, https://doi.org/10.1016/0005-2744(67)90214-8.

    Article  CAS  PubMed  Google Scholar 

  51. Nicholls, D. G. (1974) The influence of respiration and ATP hydrolysis on the proton-electrochemical gradient across the inner membrane of rat-liver mitochondria as determined by ion distribution, Eur. J. Biochem., 50, 305-315, https://doi.org/10.1111/j.1432-1033.1974.tb03899.x.

    Article  CAS  PubMed  Google Scholar 

  52. Nicholls, D. G. (1977) The effective proton conduction of the inner membrane of mitochondria from brown adipose tissue. Dependency on proton electrochemical potential gradient, Eur. J. Biochem., 77, 349-356, https://doi.org/10.1111/j.1432-1033.1977.tb11674.x.

    Article  CAS  PubMed  Google Scholar 

  53. Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijevic, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. N., Smith, A. C., Eyassu, F., Shirley, R., Hu, C. H., Dare, A. J., James, A. M., Rogatti, S., Hartley, R. C., Eaton, S., Costa, A. S., Brookes, P. S., Davidson, S. M., Duchen, M. R., Saeb-Parsy, K., Shattock, M. J., Robinson, A. J., Work, L. M., Frezza, C., Krieg, T., and Murphy, M. P. (2014) Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS, Nature, 515, 431-435, https://doi.org/10.1038/nature13909.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  54. Brockmann, K., Bjornstad, A., Dechent, P., Korenke, C. G., Smeitink, J., Trijbels, J. M., Athanassopoulos, S., Villagran, R., Skjeldal, O. H., Wilichowski, E., Frahm, J., and Hanefeld, F. (2002) Succinate in dystrophic white matter: a proton magnetic resonance spectroscopy finding characteristic for complex II deficiency, Ann. Neurol., 52, 38-46, https://doi.org/10.1002/ana.10232.

    Article  CAS  PubMed  Google Scholar 

  55. Mills, E. L., Kelly, B., Logan, A., Costa, A. S., Varma, M., Bryant, C. E., Tourlomousis, P., Dabritz, J. H., Gottlieb, E., Latorre, I., Corr, S. C., McManus, G., Ryan, D., Jacobs, H. T., Szibor, M., Xavier, R. J., Braun, T., Frezza, C., Murphy, M. P., and O’Neill, L. A. (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages, Cell, 167, 457-470.e413, https://doi.org/10.1016/j.cell.2016.08.064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Starkov, A. A., Fiskum, G., Chinopoulos, C., Lorenzo, B. J., Browne, S. E., Patel, M. S., and Beal, M. F. (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species, J. Neurosci., 24, 7779-7788, https://doi.org/10.1523/JNEUROSCI.1899-04.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lambert, A. J., Buckingham, J. A., Boysen, H. M., and Brand, M. D. (2010) Low complex I content explains the low hydrogen peroxide production rate of heart mitochondria from the long-lived pigeon, Columba livia, Aging Cell, 9, 78-91, https://doi.org/10.1111/j.1474-9726.2009.00538.x.

    Article  CAS  PubMed  Google Scholar 

  58. Lesnefsky, E. J., Chen, Q., and Hoppel, C. L. (2016) Mitochondrial metabolism in aging heart, Circ. Res., 118, 1593-1611, https://doi.org/10.1161/CIRCRESAHA.116.307505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Perevoshchikova, I. V., Quinlan, C. L., Orr, A. L., Gerencser, A. A., and Brand, M. D. (2013) Sites of superoxide and hydrogen peroxide production during fatty acid oxidation in rat skeletal muscle mitochondria, Free Radic. Biol. Med., 61, 298-309, https://doi.org/10.1016/j.freeradbiomed.2013.04.006.

    Article  CAS  PubMed  Google Scholar 

  60. Seifert, E. L., Estey, C., Xuan, J. Y., and Harper, M.-E. (2010) Electron transport chain-dependent and -independent mechanisms of mitochondrial H2O2 emission during long-chain fatty acid oxidation, J. Biol. Chem., 285, 5748-5758, https://doi.org/10.1074/jbc.M109.026203.

    Article  CAS  PubMed  Google Scholar 

  61. Lopez-Torres, M., Gredilla, R., Sanz, A., and Barja, G. (2002) Influence of aging and long-term caloric restriction on oxygen radical generation and oxidative DNA damage in rat liver mitochondria, Free Radic. Biol. Med., 32, 882-889, https://doi.org/10.1016/S0891-5849(02)00773-6.

    Article  CAS  PubMed  Google Scholar 

  62. Dalle-Donne, I., Giustarini, D., Colombo, R., Rossi, R., and Milzani, A. (2003) Protein carbonylation in human diseases, Trends Mol. Med., 9, 169-176, https://doi.org/10.1016/S1471-4914(03)00031-5.

    Article  CAS  PubMed  Google Scholar 

  63. Shabalina, I. G., and Nedergaard, J. (2011) Mitochondrial ('mild') uncoupling and ROS production: physiologically relevant or not? Biochem. Soc. Trans., 39, 1305-1309, https://doi.org/10.1042/BST0391305.

    Article  CAS  PubMed  Google Scholar 

  64. Bhattacharya, A., Lustgarten, M., Shi, Y., Liu, Y., Jang, Y. C., Pulliam, D., Jernigan, A. L., and Van Remmen, H. (2011) Increased mitochondrial matrix-directed superoxide production by fatty acid hydroperoxides in skeletal muscle mitochondria, Free Radic. Biol. Med., 50, 592-601, https://doi.org/10.1016/j.freeradbiomed.2010.12.014.

    Article  CAS  PubMed  Google Scholar 

  65. Iacono, L. L., Boczkowski, J., Zini, R., Salouage, I., Berdeaux, A., Motterlini, R., and Morin, D. (2011) A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species, Free Radic. Biol. Med., 4, 4, https://doi.org/10.1016/j.freeradbiomed.2011.02.033.

    Article  CAS  Google Scholar 

  66. Lambert, A. J., and Brand, M. D. (2009) Reactive oxygen species production by mitochondria, Methods Mol. Biol., 554, 165-181, https://doi.org/10.1007/978-1-59745-521-3_11.

    Article  CAS  PubMed  Google Scholar 

  67. Perez, V. I., Bokov, A., Van Remmen, H., Mele, J., Ran, Q., Ikeno, Y., and Richardson, A. (2009) Is the oxidative stress theory of aging dead? Biochim. Biophys. Acta, 1790, 1005-1014, https://doi.org/10.1016/j.bbagen.2009.06.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank Aleksandra Trifunovic for providing the initial breeding pair of mtDNA mutator mice, Vladimir Skulachev for stimulating discussions, Anton A. Tonshin for technical assistance, and Sofie Wagenius for establishing and verifying mouse strains.

Funding

This study was supported by grants from the Swedish Research Council. AVK was supported by a salary from the Academic Initiative of Stockholm University.

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Authors and Affiliations

  1. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91, Stockholm, Sweden

    Irina G. Shabalina, Daniel Edgar, Natalia Gibanova, Anastasia V. Kalinovich, Natasa Petrovic, Mikhail Yu. Vyssokikh, Barbara Cannon & Jan Nedergaard

Authors
  1. Irina G. Shabalina
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  2. Daniel Edgar
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  3. Natalia Gibanova
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  4. Anastasia V. Kalinovich
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  5. Natasa Petrovic
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  6. Mikhail Yu. Vyssokikh
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  7. Barbara Cannon
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  8. Jan Nedergaard
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Contributions

BC, JN, and IGS conceived and designed the work; experiments were performed by DE and IGS (oxygen consumption and ROS), NG (oxidative stress biomarkers), AVK and MYV (ROS), NP (immunoblotting), IGS (isolation of mitochondria and membrane potential); MYV, NG, and IGS analyzed results; DE, IGS, and JN wrote the manuscript. All authors revised the manuscript and approved the final version.

Corresponding author

Correspondence to Jan Nedergaard.

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The experiments were approved by the Animal Ethics Committee of the North Stockholm region.

The authors of this work declare that they have no conflicts of interest.

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Shabalina, I.G., Edgar, D., Gibanova, N. et al. Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice. Biochemistry Moscow 89, 279–298 (2024). https://doi.org/10.1134/S0006297924020081

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  • DOI: https://doi.org/10.1134/S0006297924020081

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