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Dynamics of Mitochondrial Redox and Energy Networks: Insights from an Experimental–Computational Synergy

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Systems Biology of Metabolic and Signaling Networks

Part of the book series: Springer Series in Biophysics ((BIOPHYSICS,volume 16))

Abstract

Functionally, a cell comprises spatially distributed and compartmentalized subsystems, the dynamics of which occurs on several temporal scales. Interactivity in complex spatiotemporally organized cellular systems is fundamental to their counterintuitive behavior and one of the main reasons why their study needs mathematical modeling. But models alone are not enough; what we ultimately require is a combined experimental–theoretical approach in order to validate our models as rigorously as possible.

We explore in a detailed example the success of experimental–modeling synergy leading to the elucidation of the mechanisms involved in synchronized mitochondrial oscillations in the heart, and the discovery there of new related mechanisms. This work involves successive and iterative reciprocal potentiation of the loop via experiments and computational modeling: simulation–validation and prediction– experimentation thereby alternate so as to provide a deeper understanding of complex biological phenomena.

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References

  • Akar FG, Aon MA, Tomaselli GF, O’Rourke B (2005) The mitochondrial origin of postischemic arrhythmias. J Clin Invest 115:3527–35

    Article  PubMed  CAS  Google Scholar 

  • Aon MA, Cortassa S (1994) On the fractal nature of cytoplasm. FEBS Lett 344:1–4

    Article  PubMed  CAS  Google Scholar 

  • Aon MA, Cortassa S (1997) Dynamic biological organization. Fundamentals as applied to cellular systems. Chapman & Hall, London

    Book  Google Scholar 

  • Aon MA, Cortassa S (2009) Chaotic dynamics, noise and fractal space in biochemistry. In: Meyers R (ed) Encyclopedia of complexity and systems science. Springer, New York

    Google Scholar 

  • Aon MA, Cortassa S (2012) Mitochondrial network energetics in the heart. Wiley Interdiscip Rev Syst Biol Med 4:599–613

    Article  PubMed  CAS  Google Scholar 

  • Aon M, Thomas D, Hervagault JF (1989) Spatial patterns in a photobiochemical system. Proc Natl Acad Sci USA 86:516–9

    Article  PubMed  CAS  Google Scholar 

  • Aon MA, Cortassa S, Marban E, 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 278:44735–44

    Article  PubMed  CAS  Google Scholar 

  • Aon MA, Cortassa S, O’Rourke B (2004a) Percolation and criticality in a mitochondrial network. Proc Natl Acad Sci USA 101:4447–52

    Article  PubMed  CAS  Google Scholar 

  • Aon MA, O’Rourke B, Cortassa S (2004b) The fractal architecture of cytoplasmic organization: scaling, kinetics and emergence in metabolic networks. Mol Cell Biochem 256–257:169–84

    Article  PubMed  Google Scholar 

  • Aon MA, Cortassa S, Akar FG, O'Rourke B (2006a) Mitochondrial criticality: a new concept at the turning point of life or death. Biochim Biophys Acta 1762:232–40

    Article  PubMed  CAS  Google Scholar 

  • Aon MA, Cortassa S, O’Rourke B (2006b) The fundamental organization of cardiac mitochondria as a network of coupled oscillators. Biophys J 91:4317–27

    Article  PubMed  CAS  Google Scholar 

  • Aon MA, Cortassa S, Lemar KM, Hayes AJ, Lloyd D (2007a) Single and cell population respiratory oscillations in yeast: a 2-photon scanning laser microscopy study. FEBS Lett 581:8–14

    Article  PubMed  CAS  Google Scholar 

  • Aon MA, Cortassa S, Maack C, O'Rourke B (2007b) Sequential opening of mitochondrial ion channels as a function of glutathione redox thiol status. J Biol Chem 282:21889–900

    Article  PubMed  CAS  Google Scholar 

  • Aon MA, Cortassa S, O’Rourke B (2007a) On the network properties of mitochondria. Wiley-VCH, p 111–35

    Google Scholar 

  • Aon MA, Cortassa S, O’Rourke B (2008a) Mitochondrial oscillations in physiology and pathophysiology. Adv Exp Med Biol 641:98–117

    Article  PubMed  CAS  Google Scholar 

  • Aon MA, Roussel MR, Cortassa S, O’Rourke B, Murray DB, Beckmann M, Lloyd D (2008b) The scale-free dynamics of eukaryotic cells. PLoS One 3:e3624

    Article  PubMed  Google Scholar 

  • Aon MA, Cortassa S, Akar FG, Brown DA, Zhou L, O'Rourke B (2009) From mitochondrial dynamics to arrhythmias. Int J Biochem Cell Biol 41:1940–8

    Article  PubMed  CAS  Google Scholar 

  • Biary N, Xie C, Kauffman J, Akar FG (2011) Biophysical properties and functional consequences of reactive oxygen species (ROS)-induced ROS release in intact myocardium. J Physiol 589:5167–79

    PubMed  CAS  Google Scholar 

  • Borecky J, Jezek P, Siemen D (1997) 108-pS channel in brown fat mitochondria might Be identical to the inner membrane anion channel. J Biol Chem 272:19282–9

    PubMed  CAS  Google Scholar 

  • Brown DA, Aon MA, Frasier CR, Sloan RC, Maloney AH, Anderson EJ, O’Rourke B (2010) Cardiac arrhythmias induced by glutathione oxidation can be inhibited by preventing mitochondrial depolarization. J Mol Cell Cardiol 48:673–9

    Article  PubMed  CAS  Google Scholar 

  • Cortassa S, Sun H, Kernevez JP, Thomas D (1990) Pattern formation in an immobilized bienzyme system. A morphogenetic model. Biochem J 269:115–22

    PubMed  CAS  Google Scholar 

  • Cortassa S, Aon MA, Marban E, Winslow RL, O’Rourke B (2003) An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. Biophys J 84:2734–55

    Article  PubMed  CAS  Google Scholar 

  • Cortassa S, Aon MA, Winslow RL, O’Rourke B (2004) A mitochondrial oscillator dependent on reactive oxygen species. Biophys J 87:2060–73

    Article  PubMed  CAS  Google Scholar 

  • Cortassa S, Aon MA, O’Rourke B, Jacques R, Tseng HJ, Marban E, Winslow RL (2006) A computational model integrating electrophysiology, contraction, and mitochondrial bioenergetics in the ventricular myocyte. Biophys J 91:1564–89

    Article  PubMed  CAS  Google Scholar 

  • Cortassa S, Aon MA, Iglesias AA, Aon JC, Lloyd D (2012) An introduction to metabolic and cellular engineering, 2nd edn. World Scientific, Singapore

    Google Scholar 

  • Dzeja PP, Terzic A (2003) Phosphotransfer networks and cellular energetics. J Exp Biol 206:2039–47

    Article  PubMed  CAS  Google Scholar 

  • Feder J (1988) Fractals. Plenum, New York

    Book  Google Scholar 

  • Gustafsson AB, Gottlieb RA (2008) Heart mitochondria: gates of life and death. Cardiovasc Res 77:334–43

    Article  PubMed  CAS  Google Scholar 

  • Kembro JM, Aon MA, Winslow RL, O'Rourke B, Cortassa S (2013) Integrating mitochondrial energetics, redox and ROS metabolic networks: a two-compartment model. Biophys J 104:332–343

    Article  PubMed  CAS  Google Scholar 

  • Lederer WJ, Nichols CG, Smith GL (1989) The mechanism of early contractile failure of isolated rat ventricular myocytes subjected to complete metabolic inhibition. J Physiol 413:329–49

    PubMed  CAS  Google Scholar 

  • Lemar KM, Aon MA, Cortassa S, O’Rourke B, Muller CT, Lloyd D (2007) Diallyl disulphide depletes glutathione in Candida albicans: oxidative stress-mediated cell death studied by two-photon microscopy. Yeast 24:695–706

    Article  PubMed  CAS  Google Scholar 

  • Lloyd D, Cortassa S, O’Rourke B, Aon MA (2012) What yeast and cardiomyocytes share: ultradian oscillatory redox mechanisms of cellular coherence and survival. Integr Biol (Camb) 4:65–74

    Article  CAS  Google Scholar 

  • Mandelbrot BB (1977) The fractal geometry of nature. W.H. Freeman, New York

    Google Scholar 

  • Meinhardt H (1982) Models of biological pattern formation. Academic, London

    Google Scholar 

  • Nicolis G, Prigogine I (1977) Self-organization in nonequilibrium systems : from dissipative structures to order through fluctuations. Wiley, New York, p 491

    Google Scholar 

  • Noma A (1983) ATP-regulated K+ channels in cardiac muscle. Nature 305:147–8

    Article  PubMed  CAS  Google Scholar 

  • O'Rourke B, Cortassa S, Aon MA (2005) Mitochondrial ion channels: gatekeepers of life and death. Physiology (Bethesda) 20:303–15

    Article  Google Scholar 

  • Romashko DN, Marban E, O’Rourke B (1998) Subcellular metabolic transients and mitochondrial redox waves in heart cells. Proc Natl Acad Sci USA 95:1618–23

    Article  PubMed  CAS  Google Scholar 

  • Sasaki N, Sato T, Marban E, O'Rourke B (2001) ATP consumption by uncoupled mitochondria activates sarcolemmal K(ATP) channels in cardiac myocytes. Am J Physiol Heart Circ Physiol 280:H1882–8

    PubMed  CAS  Google Scholar 

  • Schroeder M (1991) Fractals, chaos, power laws. Minutes from an infinite paradise. W.H. Freeman and Company, New York

    Google Scholar 

  • Slodzinski MK, Aon MA, O’Rourke B (2008) Glutathione oxidation as a trigger of mitochondrial depolarization and oscillation in intact hearts. J Mol Cell Cardiol 45:650–60

    Article  PubMed  CAS  Google Scholar 

  • Stauffer D, Aharony A (1994) Introduction to percolation theory. Taylor & Francis, London

    Google Scholar 

  • Turing AM (1952) The chemical basis of morphogenesis. Phil Trans R Soc Lond B237:37–72

    CAS  Google Scholar 

  • Wei AC, Aon MA, O’Rourke B, Winslow RL, Cortassa S (2011) Mitochondrial energetics, pH regulation, and Ion dynamics: a computational-experimental approach. Biophys J 100:2894–903

    Article  PubMed  CAS  Google Scholar 

  • West BJ (1999) Physiology, promiscuity and prophecy at The Millennium: A tale of tails. World Scientific, Singapore

    Book  Google Scholar 

  • Zhou L, Cortassa S, Wei AC, Aon MA, Winslow RL, O’Rourke B (2009) Modeling cardiac action potential shortening driven by oxidative stress-induced mitochondrial oscillations in guinea pig cardiomyocytes. Biophys J 97:1843–52

    Article  PubMed  CAS  Google Scholar 

  • Zhou L, Aon MA, Almas T, Cortassa S, Winslow RL, O'Rourke B (2010) A reaction–diffusion model of ROS-induced ROS release in a mitochondrial network. PLoS Comput Biol 6:e1000657

    Article  PubMed  Google Scholar 

  • Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ (2000) Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 192:1001–14

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was performed with the financial support of R21HL106054 and R01-HL091923 from NIH.

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Authors and Affiliations

  1. Division of Cardiology, Johns Hopkins University, Baltimore, MD, 21205, USA

    Sonia Cortassa & Miguel A. Aon

Authors
  1. Sonia Cortassa
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  2. Miguel A. Aon
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Correspondence to Miguel A. Aon .

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Editors and Affiliations

  1. School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA

    Miguel A. Aon

  2. Laboratory of Fundamental and Applied Bi, Inserm U1055 and University Joseph Fourier, Grenoble, Grenoble cedex 9, France

    Valdur Saks

  3. Laboratory of Fundamental and Applied Bi, Inserm U1055 and University Joseph Fourier, Grenoble, Grenoble cedex 9, France

    Uwe Schlattner

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Cortassa, S., Aon, M.A. (2014). Dynamics of Mitochondrial Redox and Energy Networks: Insights from an Experimental–Computational Synergy. In: Aon, M., Saks, V., Schlattner, U. (eds) Systems Biology of Metabolic and Signaling Networks. Springer Series in Biophysics, vol 16. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38505-6_5

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