Is There a Mitochondrial Clock?

Abstract

A mitochondrial oscillator dependent on reactive oxygen species (ROS) was first described in heart cells. Available evidence now indicates that mitochondrial energetic variables oscillate autonomously as part of a network of coupled oscillators under both physiological and pathological conditions. Moreover, emerging experimental and theoretical evidence indicates that mitochondrial network oscillations exhibit a wide range of frequencies, from milliseconds to hours, instead of a dominant frequency. With metabolic stress, the frequency spectrum narrows and a dominant oscillatory frequency appears, indicating the transition from physiological to pathophysiological behavior.

Here we show that in the pathophysiological regime the mitochondrial oscillator of heart cells is temperature compensated within the range of 25–37°C with a Q10 = 1.13. At temperatures higher than 37°C, the oscillations stop after a few cycles, whereas at temperatures lower than 25°C the oscillations are asynchronous. Using our mitochondrial oscillator model we show that this temperature compensation can be explained by kinetic compensation. Furthermore, we show that in the physiological domain temperature compensation acts to preserve the broad range of frequencies exhibited by the network of coupled mitochondrial oscillators.

The results obtained indicate that the mitochondrial network behaves with the characteristics of a biological clock, giving rise to the intriguing hypothesis that it may function as an intracellular timekeeper across multiple time scales.

Keywords

Mitochondrial oscillations temperature compensation biological clocks membrane potential reactive oxygen species power spectral and relative dispersional analyses fractal dynamics 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anderson, R. W., Laval-Martin, D. L. and Edmunds, L. N., Jr. (1985). Cell cycle oscillators. Temperature compensation of the circadian rhythm of cell division in Euglena. Exp Cell Res 157, 144–158.PubMedCrossRefGoogle Scholar
  2. Aon, M. A., Cortassa, S., Marban, E. and O’Rourke, B. (2003). Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes. J Biol Chem 278, 44735–44744.PubMedCrossRefGoogle Scholar
  3. Aon, M. A., Cortassa, S. and O’Rourke, B. (2004). Percolation and criticality in a mitochondrial network. Proc Natl Acad Sci USA 101, 4447–4452.PubMedCrossRefGoogle Scholar
  4. Aon, M. A., Cortassa, S. and O’Rourke, B. (2006). The fundamental organization of cardiac mitochondria as a network of coupled oscillators. Biophys J 91, 4317–4327.PubMedCrossRefGoogle Scholar
  5. Aon, M. A., Cortassa, S. and O’Rourke, B. (2007a). On the network properties of mitochondria. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.Google Scholar
  6. Aon, M. A., Cortassa, S. and O’Rourke, B. (2007b). Mitochondrial oscillations in physiology and pathophysiology. Austin, TX: Landes Bioscience.Google Scholar
  7. Balaban, R. S., Nemoto, S. and Finkel, T. (2005). Mitochondria, oxidants, and aging. Cell 120, 483–495.PubMedCrossRefGoogle Scholar
  8. Beavis, A. D. and Powers, M. (2004). Temperature dependence of the mitochondrial inner membrane anion channel: the relationship between temperature and inhibition by magnesium. J Biol Chem 279, 4045–4050.PubMedCrossRefGoogle Scholar
  9. Betz, A. and Chance, B. (1965). Influence of Inhibitors and temperature on the oscillation of reduced pyridine nucleotides in yeast cells. Arch Biochem Biophys 109, 579–584.PubMedCrossRefGoogle Scholar
  10. Cadenas, E. (2004). Mitochondrial free radical production and cell signaling. Mol Aspects Med 25, 17–26.PubMedCrossRefGoogle Scholar
  11. Casolo, G., Balli, E., Taddei, T., Amuhasi, J. and Gori, C. (1989). Decreased spontaneous heart rate variability in congestive heart failure. Am J Cardiol 64, 1162–1167.PubMedCrossRefGoogle Scholar
  12. Chance, B. and Yoshioka, T. (1966). Sustained oscillations of ionic constituents of mitochondria. Arch Biochem Biophys 117, 451–465.PubMedCrossRefGoogle Scholar
  13. Cortassa, S., Aon, M. A., Marban, E., Winslow, R. L. and O’Rourke, B. (2003). An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. Biophys J 84, 2734–2755.PubMedCrossRefGoogle Scholar
  14. Cortassa, S., Aon, M. A., Winslow, R. L. and O’Rourke, B. (2004). A mitochondrial oscillator dependent on reactive oxygen species. Biophys J 87, 2060–2073.PubMedCrossRefGoogle Scholar
  15. Droge, W. (2002). Free radicals in the physiological control of cell function. Physiol Rev 82, 47–95.PubMedGoogle Scholar
  16. Edmunds, L. N., Jr. (1988). Cellular and molecular basis of biological clocks: models and mechanisms for circadian timekeeping. New York: Springer.Google Scholar
  17. Ewing, D. J. (1991). Heart rate variability: an important new risk factor in patients following myocardial infarction. Clin Cardiol 14, 683–685.PubMedCrossRefGoogle Scholar
  18. Finkel, T. and Holbrook, N. J. (2000). Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247.PubMedCrossRefGoogle Scholar
  19. Finkel, T. (2005). Opinion: radical medicine: treating ageing to cure disease. Nat Rev Mol Cell Biol 6, 971–976.PubMedCrossRefGoogle Scholar
  20. Franck, U. F. (1980). The Teorell membrane oscillator–a complete nerve model. Ups J Med Sci 85, 265–282.PubMedCrossRefGoogle Scholar
  21. Goldberger, A. L., Bhargava, V., West, B. J. and Mandell, A. J. (1985). On a mechanism of cardiac electrical stability. The fractal hypothesis. Biophys J 48, 525–528.PubMedCrossRefGoogle Scholar
  22. Haddad, J. J. (2004). Oxygen sensing and oxidant/redox-related pathways. Biochem Biophys Res Commun 316, 969–977.PubMedCrossRefGoogle Scholar
  23. Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. J Gerontol 11, 298–300.PubMedGoogle Scholar
  24. Harman, D. (1972). The biologic clock: the mitochondria? J Am Geriatr Soc 20, 145–147.PubMedGoogle Scholar
  25. Kirkwood, T. (1999). Time of our lives: the science of human aging. New York: Oxford University Press.Google Scholar
  26. Kirkwood, T. B. (2005). Understanding the odd science of aging. Cell 120, 437–447.PubMedCrossRefGoogle Scholar
  27. Klevecz, R. R., Bolen, J., Forrest, G. and Murray, D. B. (2004). A genome wide oscillation in transcription gates DNA replication and cell cycle. Proc Natl Acad Sci USA 101, 1200–1205.PubMedCrossRefGoogle Scholar
  28. Kuramoto, Y. (1984). Chemical oscillations, waves, and turbulence. Berlin: Springer.Google Scholar
  29. Lane, N. (2002). Oxygen: the molecule that made the world. New York: Oxford University Press.Google Scholar
  30. Lane, N. (2005). Power, sex, suicide: mitochondria and the meaning of life. Oxford: Oxford University Press.Google Scholar
  31. Lloyd, D. (1998). Circadian and ultradian clock-controlled rhythms in unicellular microorganisms. Adv Microb Physiol 39, 291–338.PubMedCrossRefGoogle Scholar
  32. Lloyd, D. (2007). Respiratory oscillations in yeast. Austin, TX: Landes Bioscience.Google Scholar
  33. Lloyd, D. and Murray, D. B. (2006). The temporal architecture of eukaryotic growth. FEBS Lett 580, 2830–2835.PubMedCrossRefGoogle Scholar
  34. Lloyd, D. and Murray, D. B. (2007). Redox rhythmicity: clocks at the core of temporal coherence. BioEssays 29, 465–473.PubMedCrossRefGoogle Scholar
  35. Lloyd, D., Aon, M. A. and Cortassa, S. (2001). Why homeodynamics, not homeostasis? ScientificWorldJournal 1, 133–145.PubMedCrossRefGoogle Scholar
  36. Mair, T., Warnke, C., Tsuji, K. and Muller, S. C. (2005). Control of glycolytic oscillations by temperature. Biophys J 88, 639–646.PubMedCrossRefGoogle Scholar
  37. Marin-Garcia, J. and Goldenthal, M. J. (2004). Heart mitochondria signaling pathways: appraisal of an emerging field. J Mol Med 82, 565–578.PubMedCrossRefGoogle Scholar
  38. Morel, Y. and Barouki, R. (1999). Repression of gene expression by oxidative stress. Biochem J 342(Pt 3), 481–496.PubMedCrossRefGoogle Scholar
  39. Murray, D. B., Roller, S., Kuriyama, H. and Lloyd, D. (2001). Clock control of ultradian respiratory oscillation found during yeast continuous culture. J Bacteriol 183, 7253–7259.PubMedCrossRefGoogle Scholar
  40. Pittendrigh, C. S. (1993). Temporal organization: reflections of a Darwinian clock-watcher. Annu Rev Physiol 55, 16–54.PubMedCrossRefGoogle Scholar
  41. Roussel, M. R. and Lloyd, D. (2007). Observation of a chaotic multioscillatory metabolic attractor by real-time monitoring of a yeast continuous culture. FEBS J 274, 1011–1018.PubMedCrossRefGoogle Scholar
  42. Ruoff, P., Christensen, M. K., Wolf, J. and Heinrich, R. (2003). Temperature dependency and temperature compensation in a model of yeast glycolytic oscillations. Biophys Chem 106, 179–192.PubMedCrossRefGoogle Scholar
  43. Skinner, J. E., Pratt, C. M. and Vybiral, T. (1993). A reduction in the correlation dimension of heartbeat intervals precedes imminent ventricular fibrillation in human subjects. Am Heart J 125, 731–743.PubMedCrossRefGoogle Scholar
  44. Strogatz, S. H. (2003). Sync: the emerging science of spontaneous order. New York: Hyperion.Google Scholar
  45. Sweeney, B. M. and Hastings, J. W. (1960). Effects of temperature upon diurnal rhythms. Cold Spring Harb Symp Quant Biol 25, 87–104.PubMedGoogle Scholar
  46. Turrens, J. F. (2003). Mitochondrial formation of reactive oxygen species. J Physiol 552, 335–344.PubMedCrossRefGoogle Scholar
  47. West, B. J. (1999). Physiology, promiscuity and prophecy at The Millennium: A tale of tails. Singapore: World Scientific.Google Scholar
  48. Winfree, A. T. (1967). Biological rhythms and the behavior of populations of coupled oscillators. J Theor Biol 16, 15–42.PubMedCrossRefGoogle Scholar
  49. Wright, A. F., Jacobson, S. G., Cideciyan, A. V., Roman, A. J., Shu, X., Vlachantoni, D., McInnes, R. R. and Riemersma, R. A. (2004). Lifespan and mitochondrial control of neurodegeneration. Nat Genet 36, 1153–1158.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V 2008

Authors and Affiliations

  1. 1.Institute of Molecular CardiobiologyThe Johns Hopkins UniversityBaltimore

Personalised recommendations