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Membrane associated complexes : new approach to calcium dynamics modelling

  • M. Dyzma (a1), P. Szopa (a1) (a2) and B. Kaźmierczak (a1)


Mitochondria are one of the most important organelles determining Ca2+ regulatory pathway in the cell. Recent experiments suggested the existence of cytosolic microdomains with locally elevated calcium concentration (CMDs) in the nearest vicinity of the outer mitochondrial membrane (OMM). These intermediate physical connections between endoplasmic reticulum (ER) and mitochodria are called MAM (mitochondria-associated ER membrane) complexes.

The aim of this paper is to take into account the direct calcium flow from ER to mitochondria implied by the existence of MAMs and perform detailed numerical analysis of the influence of this flow on the type and shape of calcium oscillations. Depending on the permeability of MAMs interface and ER channels, different patterns of oscillations appear (simple, bursting and chaotic). For some parameters the oscillatory pattern disappear and the system tends to a steady state with extremely high calcium level in mitochondria, which can be interpreted as a crucial point at the beginning of an apoptotic pathway.


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[1] Clapham, D.E.. Calcium signaling. Cell, 131 (2007), 10471058.
[2] Laude, A.J., Simpson, A.W.M.. Compartmentalized signalling : Ca2+ compartments, microdomains and the many facets of Ca2+ signalling. FEBS J., 276 (2009), 18001816.
[3] Montell, C.. The latest waves in calcium signaling. Cell, 122 (2005), 157163.
[4] Oster, A.M., Thomas, B., Terman, D., Fall, C.P.. The low conductance mitochondrial permeability transition pore confers excitability and CICR wave propagation in a computational model. J Theor Biol, 273 (2011), 216231.
[5] Hajnóczky, G., Csordás, G., Madesh, M., Pacher, P.. The machinery of local Ca2+ signalling between sarco-endoplasmic reticulum and mitochondria. J. Physiology, 529 (2000), 6981.
[6] Chipuk, J.E., Bouchier-Hayes, L., Green, D.R.. Mitochondrial outer membrane permeabilization during apoptosis : the innocent bystander scenario. Cell Death Differ., 13 (2006) 13961400.
[7] Tait, S.W., Parsons, M.J., Llambi, F., Bouchier-Hayes, L., Connell, S., Munoz-Pinedo, C., Green, D.R.. Resistance to caspase-independent cell death requires persistence of intact mitochondria. Dev. Cell, 18 (2010) 802-81.
[8] Hajnóczky, G., Csordás, G., Das, S., Garcia-Perez, C., Saotome, M., Roy, S.S., Yi, M.. Mitochondrial calcium signalling and cell death : approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium, 40 (2006) 553560.
[9] Borghans, J.A.M., Dupont, G., Goldbeter, A.. Complex intracellular calcium oscillations. A theoretical exploration of possible mechanisms. Biophysical Chemistry, 66 (1997) 2541.
[10] Marhl, M., Haberichter, T., Brumen, M., Heinrich, R.. Complex calcium oscillations and the role of mitochondria and cytosolic proteins. Biosystems, 57 (2000) 7586.
[11] Csordás, G., Várnai, P., Golenár, T., Roy, S., Purkins, G., Schneider, T.G., Balla, T., Hajnóczky, G.. Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell, 39 (2010) 121132.
[12] Dennis, E.A., Kennedy, E.P.. Intracellular sites of lipid synthesis and the biogenesis of mitochondria. J Lipid Res, 13 (1972) 263267.
[13] Rusinol, A.E., Cui, Z., Chen, M.H., Vance, J.E.. A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins. J Biol Chem, 269 (1994) 2749427502.
[14] Giorgi, C., De Stefani, D., Bononi, A., Rizzuto, R., Pinton, P.. Structural and functional link between the mitochondrial network and the endoplasmic reticulum. Int J Biochem Cell Biol, 41 (2009) 18171827.
[15] Lebiedzinska, M., Szabadkai, G., Jones, A.W.E., Duszynski, J., Wieckowski, M.R.. Interactions between the endoplasmic reticulum, mitochondria, plasma membrane and other subcellular organelles. Int J Biochem Cell Biol, 41 (2009) 18051816.
[16] Giacomello, M., Drago, I., Bortolozzi, M., Scorzeto, M., Gianelle, A., Pizzo, P., Pozzan, T.. Ca2+ hot spots on the mitochondrial surface are generated by Ca2+ mobilization from stores, but not by activation of store-operated Ca2+ channels. Mol Cell., 38(2) (2010) 280290.
[17] Csordás, G., Renken, C., Várnai, P., Walter, L., Weaver, D., Buttle, K.F., Balla, T., Mannella, C.A., Hajnóczky, G.. Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol, 174 (2006) 915921.
[18] Hayashi, T., Rizzuto, R., Hajnóczky, G., Su, T.-P.. MAM : more than just a housekeeper. Trends Cell Biol, 19 (2009) 8188.
[19] Schuster, S., Marhl, M., Höfer, T.. Modelling of simple and complex calcium oscillations. From single-cell responses to intercellular signalling. Eur J Biochem, 269 (2002) 13331355.
[20] D. Hariprasad, M. McNulty, J. Shi, P. Tian. Three-pool model of calcium signaling. (2009).
[21] Marhl, M., Schuster, S., Brumen, M.. Mitochondria as an important factor in the maintenance of constant amplitudes of cytosolic calcium oscillations. Biophysical Chemistry, 71 (1998) 125132.
[22] H. Coe, M. Michalak. Calcium binding chaperones of the endoplasmic reticulum. Gen Physiol Biophys, 28 Spec No Focus (2009) F96–F103.
[23] B. Schwaller. Cytosolic Ca2+ buffers. Cold Spring Harb Perspect Biol, 2(11) a004051.
[24] Parekh, A.B.. Mitochondrial regulation of intracellular Ca2+ signaling : more than just simple Ca2+ buffers. News Physiol Sci, 18 (2003) 252256.
[25] J. Keener, J. Sneyd. Mathematical Physiology, Springer, New York, 1998.
[26] Sneyd, J., Duffy, A., Dale, P.D.. Traveling Waves in Buffered Systems : Applications to Calcium Waves. SIAM J. Appl. Math., 58 (1998) 11781192.
[27] Skupin, A., Falcke, M.. From puffs to global Ca2+ signals : how molecular properties shape global signals. Chaos, 19 (2009) 037111.
[28] Hoogenboom, B.W., Suda, K., Engel, A., Fotiadis, D.. The supramolecular assemblies of voltage-dependent anion channels in the native membrane. J Mol Biol., 370 (2007) 246255.
[29] Shoshan-Barmatz, V., De Pinto, V., Zweckstetter, M., Raviv, Z., Keinan, N., Arbel, N.. VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med., 31 (2010) 227285.
[30] Dupont, G., Combettes, L.. What can we learn from the irregularity of Ca2+ oscillations ?. Chaos, 19 (2009) 037112.
[31] Wagner, J., Keizer, J.. Effects of rapid buffers on Ca2+ diffusion and Ca2+ oscillations. Biophys J., 67 (1994) 447456.
[32] Dawson, A.P., Rich, G.T., Loomis-Husselbee, J.W.. Estimation of the free [Ca2+] gradient across endoplasmic reticulum membranes by a null-point method. Biochem J., 310 (1995) 371374.
[33] Hoth, M., Fanger, C.M., Lewis, R.S.. Mitochondrial regulation of store-operated calcium signaling in T lymphocytes. J Cell Biol., 137 (1997) 633648.
[34] Li, Y.-X., Keizer, J., Stojilkovic, S.S., Rinzel, J.. Calcium excitability of the ER membrane : an explanation for IP3-induced Ca2+ oscillations. Am J Physiol Cell Physiol, 269 (1995) C1079C1092.
[35] Sneyd, J., Tsaneva-Atanasova, K., Yule, D. I., Thompson, J. L., Shuttleworth, T. J.. Control of calcium oscillations by membrane fluxes. Proc Natl Acad Sci USA, 101 (2004) 13921396.
[36] Babcock, D.F., Hille, B.. Mitochondrial oversight of cellular Ca2+ signaling. Curr. Opin. Neurobiol., 8 (1998) 398404.
[37] Falcke, M.. Reading the patterns in living cells - the physics of Ca2+ signaling. Advances in Physics, 53 (2004) 255440.
[38] Rasola, A., Bernardi, P.. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis, 12 (2007) 815833.
[39] Babcock, D.F., Herrington, J., Goodwin, P.C., Park, Y.B., Hille, B.. Mitochondrial participation in the intracellular Ca2+ network. J. Cell Biol, 136 (1997) 833844.
[40] Hehl, S., Golard, A., Hille, B.. Involvement of mitochondria in intracellular calcium sequestration by rat gonadotropes. Cell Calcium, 20 (1996) 515524.
[41] Svichar, N., Shishkin, V., Kostyuk, P.. Mitochondrial participation in modulation of calcium transients in DRG neurons. Neuroreport, 10 (1999) 12571261.
[42] V.V. Chepyzhov, M.I. Vishik. Attractors for Equations of Mathematical Physics. American Mathematical Society, Providence RI, 2002.
[43] W. Govaerts, Yu.A. Kuznetsov,
[44] Joseph, S.K., Hajnóczky, G.. IP3 receptors in cell survival and apoptosis : Ca2+ release and beyond. Apoptosis, 12 (2007) 951968.
[45] Roy, S.S., Hajnóczky, G.. Calcium, mitochondria and apoptosis studied by fluorescence measurements. Methods, 46 (2008) 213223.
[46] Rizzuto, R., Pinton, P., Ferrari, D., Chami, M., Szabadkai, G., Magalhães, P.J., Di Virgilio, F., Pozzan, T.. Calcium and apoptosis : facts and hypotheses. Oncogene, 22 (2003) 86198627.
[49] H. Kantz, T. Schreiber. Nonlinear Time Series Analysis, Cambridge University Press, Cambridge, 2004.
[50] Özer, A.B., Akin, E.. Tools for detecting chaos. SAU Fen Bilimleri Enstitusu Dergisi, 9 (2005) 6066.
[51] Park, B.J., Lee, D.G., Yu, J.R., Jung, S.K., Choi, K., Lee, J., Lee, J., Kim, Y.S., Lee, J.I., Kwon, J.Y., Lee, J., Singson, A., Song, W.K., Eom, S.H., Park, C.S., Kim, D.H., Bandyopadhyay, J., Ahnn, J.. Calreticulin, a calcium-binding molecular chaperone, is required for stress response and fertility in Caenorhabditis elegans. Mol Biol Cell., 12(9) (2001) 28352845.
[52] Ellgaard, L., Helenius, A.. ER quality control : towards an understanding at the molecular level. Current Opinion in Cell Biology, 13(4) (2001) 431437.
[53] Anelli, T., Alessio, M., Mezghrani, A., Simmen, T., Talamo, F., Bachi, A., Sitia, R.. ERp44, a novel endoplasmic reticulum folding assistant of thethioredoxin family. The EMBO Journal, 21 (2002) 835844.
[54] Hayashi, T., Su, T.P.. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell, 131(3) (2007) 596610.
[55] Jethmalani, S.M., Henle, K.J.. Calreticulin associates with stress proteins : implications for chaperone function during heat stress. J Cell Biochem., 69(1) (1998) 3043.
[56] Mizzen, L.A., Kabiling, A.N., Welch, W.J.. The two mammalian mitochondrial stress proteins, grp 75 and hsp 58, transiently interact with newly synthesized mitochondrial proteins. Cell Regul., 2(2) (1991) 165179.


Membrane associated complexes : new approach to calcium dynamics modelling

  • M. Dyzma (a1), P. Szopa (a1) (a2) and B. Kaźmierczak (a1)


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