Skip to main content
Log in

Mitochondrial Oxygen Radical Generation and Leak: Sites of Production in States 4 and 3, Organ Specificity, and Relation to Aging and Longevity

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Studies in heart and nonsynaptic brain mitochondria from two mammals and three birds showthat complex I generates oxygen radicals in heart and nonsynaptic brain mitochondria in States4 and 3, whereas complex III does it only in heart mitochondria and only in State 4. Theincrease in oxygen consumption during the State 4 to 3 transition is not accompanied by aproportional increase in oxygen radical generation. This will protect mitochondria and tissuesduring bursts of activity. Comparisons between young and old rodents do not show a consistentpattern of variation in mitochondrial oxygen radical production during aging. However, allthe interspecies comparisons performed to date between different mammals, and betweenmammals and birds, agree that animals with high maximum longevities have low rates ofmitochondrial oxygen radical production, irrespective of the value of their basal specificmetabolic rate. The sites and mechanisms allowing this, the recently described low degree ofmembrane fatty acid unsaturation of longevous animals, and their relation to longevity andaging are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

REFERENCES

  • Anson, R. M., Croteau, D. L., Stierum, R. H., Fliburn, C., Parsell, R., and Bohr, V. A. (1998). Nucleic Acids Res. 26, 662-668.

    Google Scholar 

  • Austad, S. N., and Fisher, K. E. (1992). Amer. J. Primatol. 28, 251-261.

    Google Scholar 

  • Barja, G. (1998). Ann. NY Acad. Sci., 854, 224-238.

    Google Scholar 

  • Barja, G. (1999). In Methods in Aging Research (Yu, B. P. ed.), CRC Press, Boca Raton, Florida, pp. 533-548.

    Google Scholar 

  • Barja, G., and Herrero, A. (1998). J. Bioenerg. Biomembr. 30, 235-243.

    Google Scholar 

  • Barja, G., Cadenas, S., Rojas, C., López-Torres, M., and Pérez-Campo, R. (1994a). Comp. Biochem. Physiol. 108B, 501-512.

    Google Scholar 

  • Barja, G., Cadenas, S., Rojas, C., Pérez-Campo, R., and López-Torres, M. (1994b). Free Radical Res. 21, 317-328.

    Google Scholar 

  • Beckman, K. B., and Ames, B. N. (1996). Methods Enzymol. 264, 442-453.

    Google Scholar 

  • Beckman, K. B., and Ames, B. N. (1998). Physiol. Rev. 78, 547-581.

    Google Scholar 

  • Boveris, A., and Chance, B. (1973). Biochem. J. 134, 707-716.

    Google Scholar 

  • Boveris, A., Oshino, N., and Chance, B. (1972). Biochem. J. 128, 617-630.

    Google Scholar 

  • Boveris, A., Cadenas, E., and Stoppani, A. O. M. (1976). Biochem J. 156, 435-444.

    Google Scholar 

  • Brand, M. D., and Murphy, M. P. (1987). Biol. Rev. 62, 141-193.

    Google Scholar 

  • Cadenas, E., and Boveris, A. (1980). Biochem. J. 188, 31-37.

    Google Scholar 

  • Cadenas, E., Boveris, A., Ragan C. I., and Stoppani, A. O. M. (1977). Arch. Biochem. Biophys. 180, 248-257.

    Google Scholar 

  • Cadenas, S., Barja, G., Poulsen, H. E., and Loft, S. (1997). Carcinogenesis 18, 2373-2377.

    Google Scholar 

  • Chance, B. (1981). In Oxygen and Living Processes (Gilbert, D., ed.), Springer Verlag, New York, pp. 200-209.

    Google Scholar 

  • Chance, B., and Williams, G. R. (1956). Advan. Enzymol. Related Subjects Biochem. 17, 65-134.

    Google Scholar 

  • Chance, B., and Hollunger, G. J. (1961). J. Biol. Chem. 236, 1534-1543.

    Google Scholar 

  • Cino, M., and del Maestro, R. F (1989). Arch. Biochem. Biophys. 269, 623-638.

    Google Scholar 

  • Clayton, D. A., Doda, J. N., and Friedberg, E. C. (1974). Proc. Natl. Acad. Sci. U.S. 71, 2777-2781.

    Google Scholar 

  • Cortopassi, G. A., and Wang, E. (1996). Mechan. Ageing Develop. 91, 211-218.

    Google Scholar 

  • Croteau, D. L., Rhys, C. A., Hudson, E. K., Dianov, G. L., Hansford, R. G., and Bohr, V. A. (1997). J. Biol. Chem. 272, 27338-27344.

    Google Scholar 

  • Cutler, R. G. (1991). Amer. J. Clin. Nutr. 53, 373S-379S.

    Google Scholar 

  • Davies, J. A., Quintanilha, A. T., Brooks, G. A., and Packer, L. (1982). Biochem. Biophys. Res. Commun. 107, 1198-1205.

    Google Scholar 

  • Domena, J. D., Timmer, R. T., Dicharry, S. A., and Mosbaugh, D. W. (1988). Biochemistry 27, 6742-6751.

    Google Scholar 

  • Dutton, P. L., Moser, C. C., Sled, V. D., Daldal, F., and Ohnishi, T. (1998). Biochim. Biophys. Acta 1364, 245-257.

    Google Scholar 

  • Fleming, J. E., Leon, H. A., and Miquel, J. (1981). Exp. Gerontol. 16, 287-293.

    Google Scholar 

  • Floyd, R. A., Zaleska, M. M., and Harmon, H. J. (1984). In Free Radicals in Molecular Biology, Aging and Disease (Aarmstrong, D., ed.), Raven Press, New York, pp. 143-161.

    Google Scholar 

  • Forman, H. J., and Azzi, A. (1997). FASEB J. 11, 374-375.

    Google Scholar 

  • Funakaga, M. and Yielding, K. L. (1979). Biochem. Biophys. Res. Commun. 90, 582-586.

    Google Scholar 

  • García de la Asunción, J., Millan, A., Pla, R., Bruseghini, L., Esteras, A., Pallardo, F. V., Sastre, J., and Viña, J. (1996). FASEB J. 10, 333-338.

    Google Scholar 

  • Gaziano, J. M., and Hennekens, C. H. (1995). Cont. Internal Med. 7, 9-14.

    Google Scholar 

  • Gey, K. F., Puska, P., Jordan, P., Moser, U. K. (1991). Amer. J. Clin. Nutr. 53, 326-334.

    Google Scholar 

  • Goodrick, C. L. (1980). Gerontology 26, 22-33.

    Google Scholar 

  • Grigorieff, N. (1998). J. Mol. Evol. 277, 1033-1046.

    Google Scholar 

  • Guarnieri, C. C., Muscari, C., and Caldarera, C. M. (1992). In Free Radicals and Aging (Emerit, E. and Chance, B., eds.), Birkhäuser, Basel, pp. 73-77.

    Google Scholar 

  • Hansford, R. G., Hogue, B. A., and Mildaziene, V. (1997). J. Bioenerg. Biomembr. 29, 89-95.

    Google Scholar 

  • Harman, D. (1956). J. Gerontol. 11, 298-300.

    Google Scholar 

  • Harman, D. (1972). J. Amer. Geriatr. Soc. 20, 145-157.

    Google Scholar 

  • Herrero, A. and Barja, G. (1997a). Mechan. Ageing Develop. 98, 95-111.

    Google Scholar 

  • Herrero, A., and Barja, G. (1997b). J. Bioenerg. Biomembr. 29, 241-249.

    Google Scholar 

  • Herrero, A. and Barja, G. (1998). Mechan. Ageing Develop. 103, 133-146.

    Google Scholar 

  • Hiraku, Y. and Kawanishi, S. (1996). Cancer Res. 56, 5172-5178.

    Google Scholar 

  • Hinkle, P. C., Butow, R. A., Racker, E., and Chance, B. (1967). J. Biol. Chem. 242, 5169-5173.

    Google Scholar 

  • Holloszy, J. O. (1997). J. Appl. Physiol. 82, 399-403.

    Google Scholar 

  • Holloszy, J. O., Smith, E. K., Vining, M., and Adams, S. A. (1985). J. Appl. Physiol. 59, 826-831.

    Google Scholar 

  • Jackson, M. J., Edwards, R. H. T., and Symons, M. C. R. (1985). Biochim. Biophys. Acta 847, 185-190.

    Google Scholar 

  • Kwong, L. K., and Sohal, R. (1998). Arch. Biochem. Biophys. 350, 118-126.

    Google Scholar 

  • Ku, H. H., and Sohal, R. S. (1993). Mechan. Ageing Develop. 72, 67-76.

    Google Scholar 

  • Ku, H. H., Brunk, UT, and Sohal, R. S. (1993). Free Radical Biol. Med. 15, 621-627.

    Google Scholar 

  • Lai C. K., and Clark, J. B. (1979). Methods Enzymol. 55, 51-60.

    Google Scholar 

  • Lee, I. M., Sieh, C. C. H., and Paffenbarger, R. S. (1995). J. Amer. Med. Assoc. 273, 1179-1184.

    Google Scholar 

  • Lee, Y. S., Coi, J. Y., Park, M. K., Choi, E. M., Kasai, H., and Chung, M. H. (1996). Mutat. Res. 364, 227-233.

    Google Scholar 

  • Loft, S., Deng, X., Tuo, J., Wellejus, A., Sorensen, M., and Poulsen, H. E. (1999). Free Radical Res., 29, 525-539.

    Google Scholar 

  • López-Torres, M., Pérez-Campo, R., Rojas, C., Cadenas, S., and Barja, G. (1993a). Mechan. Ageing Develop. 70, 177-179.

    Google Scholar 

  • López-Torres, M., Pérez-Campo, R., Rojas, C., Cadenas, S., and Barja de Quiroga, G. (1993b). Free Radical. Biol. Med. 15, 133-142.

    Google Scholar 

  • López-Torres M., Pérez-Campo, R., Fernández, A., Barba, C., and Barja de Quiroga, G. (1993c). J. Neurosci. Res, 34, 233-242.

    Google Scholar 

  • Loschen, G., Flohé, L., and Chance, B. (1971). FEBS Lett. 18, 261-264.

    Google Scholar 

  • Loschen, G., Azzi, A., and Flohé, L. (1973). FEBS Lett. 33, 84-88.

    Google Scholar 

  • Loschen, G., Azzi, A., Richter, C., and Flohé, L. (1974). FEBS Lett. 42, 68-72.

    Google Scholar 

  • Matsuno-Yagi, A., and Hatefi, Y (1996). J. Biol. Chem. 271, 6164-6171.

    Google Scholar 

  • Mecocci, P., MacGarvey, U., Kaufman, A. E., Koontz, D., Shoffner, J. M., Wallace, D. C., and Beal, M. F. (1993). Ann. Neurol. 34, 609-616.

    Google Scholar 

  • Myers, K.A., Saffhill, R., and O'Connor, P.J. (1988). Carcinogenesis 9, 285-292.

    Google Scholar 

  • Miquel, J. (1991). Arch. Gerontol. Geriatr. 12, 99-117.

    Google Scholar 

  • Muscari, C., Frascaro, M., Guarnieri, C., and Caldarera, C.M. (1990). Biochim. Biophys. Acta 1015, 200-204.

    Google Scholar 

  • Nohl, H. (1986) In Modern Aging Research. Free Radicals, Aging and Degenerative Diseases (Johnson, J. E., Walford, R., and Harman, D. eds.), Vol. 8. Alan Liss, New York, pp.77-97.

    Google Scholar 

  • Nohl, H. (1987). FEBS Lett. 214, 269-273.

    Google Scholar 

  • Nohl, H. and Jordan, W. (1986). Biochem. Biophys. Res. Commun. 138, 533-539.

    Google Scholar 

  • Nohl, H., and Hegner, D. (1978). Eur. J. Biochem. 82, 563-567.

    Google Scholar 

  • Nohl, H. and Stolze, K. (1992). Free Radical Res. Commun. 16, 409-419.

    Google Scholar 

  • Nohl, H., Staniek, K., and Gille, L. (1997). Exp. Gerontol. 32, 485-500.

    Google Scholar 

  • Ogburn, C. E., Austad, S. N., Holmes, D. J., Kiklevich, J. V., Gollahon, K., Rabinovitch, P. S., and Martin, G,M. (1998). J. Gerontol. 53, B287-B292.

    Google Scholar 

  • Orr, W. C., and Sohal, R. S. (1994). Science 263, 1128-1130.

    Google Scholar 

  • Ozawa, T. (1995). Exp. Gerontol. 30, 269-290.

    Google Scholar 

  • Paffenbarger, R. S., Hyde, R. T., Wing, A. L., and Hsie, C. (1986). New Engl. J. Med. 314, 605-613.

    Google Scholar 

  • Pamplona, R., Prat, J., Cadenas, S., Rojas, C., Pérez-Campo, R., López-Torres, M., and Barja, G. (1996). Mechan. Ageing Develop. 86, 53-66.

    Google Scholar 

  • Pamplona, R., Portero-Otín, M., Ruiz, C., Prat, J., Bellmunt, M. J., and Barja G. (1998). J. Lipid Res. 39, 1989-1994.

    Google Scholar 

  • Pamplona, R., Portero-Otín, M., Requena, J. R., Thorpe, S. R., Herrero, A.,and Barja, G. (1999a). Mechan. Ageing Develop., 106, 283-296.

    Google Scholar 

  • Pamplona, R., Portero-Otín, M., Riba, D., Ledo, F., Gredilla, R., Herrero, A., and Barja, G.(1999b). Aging Clin. Exp. Res, 11, 44-49.

    Google Scholar 

  • Pearl, R. (1928). The Rate of Living, University of London Press, London.

    Google Scholar 

  • Pérez-Campo, R., López-Torres, M., Rojas, C., Cadenas, S., and G. Barja (1994). J. Comp. Physiol. 163, 682-689.

    Google Scholar 

  • Pérez-Campo, R., López-Torres, M., Cadenas, S., Rojas, C., and G. Barja (1998). J. Comp. Physiol. 168, 149-158.

    Google Scholar 

  • Pitkänen, S. and Robinson, B. H. (1996). J. Clin. Invest. 98, 345-351.

    Google Scholar 

  • Priemé, H., Loft, S., Nyyssönen, K., Salonen, J. T., and Poulsen, H. E. (1997). Amer. J. Clin. Nutr. 65, 503-507.

    Google Scholar 

  • Prinzinger, R. (1993). Comp. Biochem. Physiol. 105A, 609-615.

    Google Scholar 

  • Ragan, C. I. (1987). Current Topics Bioenerg. 15, 1-36.

    Google Scholar 

  • Reznick, A., and Gershon, D. (1999). In Methods in Aging Research (Yu, B. P. ed.), CRC Press, Boca Raton, Florida, pp. 167-190.

    Google Scholar 

  • Richter, C. (1995). Current Topics Bioenerg. 17, 1-19.

    Google Scholar 

  • Richter, C., Park, J. W., and Ames, B. N. (1988). Proc. Natl. Acad. Sci. U.S. 85, 6465-6467.

    Google Scholar 

  • Robinson, B. H. (1998). Biochim. Biophys. Acta 1364, 271-286.

    Google Scholar 

  • Rubner, M. (1908). Das Problem der Lebensdauer und seine Beziehungen zu Wachstum und Ernährung (R. Oldenburg, ed.), München.

  • Saul, R. L., Gee, P., and Ames, B. N. (1987). In Modern Biological Theories of Aging (Warner, H. R. ed.), Raven Press, New York, pp. 113-129.

    Google Scholar 

  • Sawada, M. and Carlsson, J. C. (1987). Mechan. Ageing Develop. 41, 125-137.

    Google Scholar 

  • Schmidt-Nielsen, K. (1984). Scaling. Why Is Animal Size so Important?, Cambridge Univ. Press, New York, pp. 106-108.

    Google Scholar 

  • Sherratt, H. S. A., Watmough, N. J., Johnson, M. A., and Turnbull, D. M. (1988). Methods Biochem. Anal. 33, 304-305.

    Google Scholar 

  • Sohal, R. S. and Weindruch, R. (1996). Science 273, 59-63.

    Google Scholar 

  • Sohal, R. S., Svensson, I., Sohal, B. H., and Brunk, U. T. (1989). Mechan. Ageing Develop. 49, 129-135.

    Google Scholar 

  • Sohal, R. S., Svensson, I., and Brunk, U. T. (1990). Mechan. Ageing Develop. 53, 209-215.

    Google Scholar 

  • Sohal, R. S., Ku, H. H., and Agarwal, S. (1993). Biochem. Biophys. Res. Commun. 196, 7-11.

    Google Scholar 

  • Sohal, R. S., Ku, H. H., Agarwal, S., Forster, M. J., and Lal, H. (1994). Mechan. Ageing Develop. 74, 121-133.

    Google Scholar 

  • Sohal, R. S., Agarwal, S., and Sohal, B. H. (1995a). Mechan. Ageing Develop. 81, 15-25.

    Google Scholar 

  • Sohal, R. S., Sohal, B. H., and Orr, W. C. (1995b). Free Radical Biol. Med. 19, 499-509.

    Google Scholar 

  • Sorgato, M. C., Sartorelli, L., Loschen, G., and Azzi, A. (1974). FEBS Lett. 45, 92-95.

    Google Scholar 

  • Souza-Pinto, N. C., Croteau, D. L., Hudson, E. K., Hansford, E. K., and Bohr, R. G. (1998). Revista de Farmacia e Bioquímica da Universidade de Sao Paulo, vol. 34, Presented at the 16-04 Symposium of the IX Biennial Meeting of the International Society for Free Radical Research, Sao Paulo, 7–11 September, 1998, pp. 73.

    Google Scholar 

  • Takeshigue, K., and Minakami, S. (1979). Biochem. J. 180, 129-135.

    Google Scholar 

  • Thyagarajan, B., Padua, R. A., and Campbell, C. (1996). J. Biol. Chem. 271, 27536-27543.

    Google Scholar 

  • Tolmasoff, J. M., Ono, T., and Cutler, R. G. (1980). Proc. Natl. Acad. Sci U.S. 77, 2777-2781.

    Google Scholar 

  • Tomkinson, A. E., Bonk, R. T., and Linn, S. (1988). J. Biol Chem. 263, 12532-12537.

    Google Scholar 

  • Tomkinson, A. E., Bonk, R. T., Kim, J., Bartfeld, N., and Linn, S. (1990). Nucleic Acid Res. 18, 929-935.

    Google Scholar 

  • Turrens, J. F. (1997). Biosci. Rep. 17, 3-8.

    Google Scholar 

  • Turrens, J. F., and Boveris, A. (1980). Biochem. J. 191, 421-427.

    Google Scholar 

  • Turrens, J. F., Alexandre, A., and Lehninger, A. L. (1985). Arch. Biochem. Biophys. 237, 408-414.

    Google Scholar 

  • Tyler, D. D. (1992). The Mitochondria in Health and Disease, VCH, New York, pp. 90, 172–188, 253, and 305–310.

    Google Scholar 

  • Tzagoloff, A. (1982). Mitochondria, Plenum Press, New York, pp. 136-137, 140–141.

    Google Scholar 

  • Von Jagow, G., and Engel, W. D. (1981). FEBS Lett. 136, 19-24.

    Google Scholar 

  • Williams, J. N. (1968). Biochim. Biophys. Acta 162, 175-181.

    Google Scholar 

  • Yu, B. P. (1995). In Handbook of Physiology, Section 11: Aging (Masoro, E. J., ed.), Oxford University Press, New York, 613-631.

    Google Scholar 

  • Zastawny, T. H., Czerwinska, B., Drzewiecka, B., and Olinski, R. (1997). Free Radical Biol. Med. 22, 101-107.

    Google Scholar 

  • Zhan, H., Sun, C. P., Liu, C. G., and Zhou, J. H. (1992). Mechan. Ageing Develop. 62, 111-116.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barja, G. Mitochondrial Oxygen Radical Generation and Leak: Sites of Production in States 4 and 3, Organ Specificity, and Relation to Aging and Longevity. J Bioenerg Biomembr 31, 347–366 (1999). https://doi.org/10.1023/A:1005427919188

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1005427919188

Navigation