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A Model of Mitochonrial Calcium Induced Calcium

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A Model of Mitochonrial Calcium Induced Calcium A MODEL OF MITOCHONRIAL CALCIUM INDUCED CALCIUM RELEASE DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Balbir Thomas, The Ohio State University 2007 Dissertation Committee: Approved by David Terman, Adviser Douglas R. Pfeiffer Adviser Edward Overman Biophysics Graduate Program Christopher P. Fall ABSTRACT Cytoplasmic calcium plays a dual role in cellular physiology. On one hand it acts as a second messenger in intra-cellular signalling, and on the other hand it is also the trigger for calcium dependent apopotosis. A mechanistic explanation of this dual role of cytoplasmic calcium was proposed by Ichas and Mazat. Their hypothesis involved the permeability transition pore was based on the observation that the permeability transition pore can exist in multiple conductance states. Specifically there exist a persistent high conductance state and a transitory low conductance state. Ichas et.al. also observed that the low conductance state is opened by a rise in mitochondrial matrix pH, in contrast to what was already know about the high conductance state, which opens in response to prolonged elevation of mitochondrial calcium. In this dissertation we build a detailed, physiological model of the mitochondrial switch between calcium signalling and cell death based on a simple three state model of the permeability transition pore. This model agrees with the substance of the Ichas and Mazat hypothesis and provides a substrate for further modeling to study the spatial and temporal dynamics of mitochondrial involvement in intracellular calcium signalling, and the interaction of mitochondria and endoplasmic reticulum during this process. ii °c Copyright by Balbir Thomas 2007 This dissertation is dedicated to Mr. Tajinder Singh iv ACKNOWLEDGMENTS I am deeply obliged to Dr. David Terman and the Biophysics graduate program for having given me the oppertunity and support in conducting this research. During this pro- cess I have had many fruitfull disccusssions with Dr. Douglas R. Pfeiffer, Dr. Edward Overman, Dr. Christopher P. Fall Dr. Abdoul Kane and Dr. Andrew Oster. I am also grateful to Cindy Bernlohr for her advise and help on many adminstrative issues. Much of the production of this dissertation, owes a debt to the multitude of open source software developers, who have made my task, considerably easier. I am also indebted to my mother for her paitence during the long years of my absence and to Marta Wojciechowska for her continual encouragement and support. v VITA May14,1970 ...............................Born-Baroda, India 1990 .......................................B.Sc.(Hons.), Human Biology 1992 .......................................M.Sc.,Biophysics 1993-1994 ..................................Technical services executive, Industrial enzyme division, Biocon, India 1995-1997 ..................................JuniorResearch Fellow, Council of Scientific and Industrial Re- search, India October 1997 - August 1998 . Software Developer and Trainer, Wintech Computers, India May1998-August1998 .....................AssistantEditor, Software Review Magazine, India August1998-present .......................GraduateAssociate, Biophysics program, Ohio State University, U.S.A vi PUBLICATIONS Instructional Publications B. Thomas, “The Markup Language Primer : SGML, XML and HTML” Software Review Magazine, August, 1998. B. Thomas “Modulo Arithematic and Public Key Cryptography” Software Review Maga- zine, August, 1998. FIELDS OF STUDY Major Field: Biophysics Studies in: Mathematical Biology Prof. David Terman Numerical Analysis Prof. Edward Overman Mitochondrial Physiology Prof. Douglas R. Pfeiffer vii TABLE OF CONTENTS Page Abstract......................................... ii Dedication........................................ iv Acknowledgments.................................... v Vita ........................................... vi ListofFigures...................................... xi Chapters: 1. INTRODUCTION ................................ 1 2. BACKGROUND ................................. 3 2.1 Introduction................................. 3 2.2 Generation of reducing equivalents . ... 5 2.3 Adenine Nucleotide Transporter . 10 2.4 CalciumUniporter ............................. 10 2.5 Sodium-CalciumExchanger . 13 2.6 IP3Receptorchannel............................ 13 2.7 SERCApump ............................... 14 2.8 SummaryofODEs............................. 15 3. MITOCHONDRIAL PROTON CURRENTS . 18 3.1 Introduction................................. 18 3.2 pH sensitive Proton currents . 20 viii 3.2.1 A pH sensitive respiratory Proton Pump . 20 3.2.2 A pH sensitive F0-F1 ATPase ................... 23 3.3 Steadystaterateequations . 25 3.3.1 Respiratoryrates. 26 3.3.2 Oxidative phosphorylation rates . 27 3.3.3 CycleFluxes............................ 27 3.3.4 CycleForces............................ 29 3.3.5 RateConstants........................... 45 3.4 Electro-neutralweakacidflux . 49 4. PERMIABILITYTRANSITIONPORE . 51 4.1 Introduction................................. 51 4.2 Threestatemodel.............................. 52 5. PORECURRENTS................................ 55 5.1 Introduction................................. 55 5.2 Calcium current through the pore . 56 5.3 Proton current through the pore . 57 6. SIMPLIFICATION ................................ 58 6.1 introduction................................. 58 6.2 Phenomenological rate equations . 58 7. RESULTS..................................... 61 7.1 pH dependent respiratory fluxes . 61 7.2 Simplification................................ 65 7.3 Mitochondrial response to cytoplasmic calcium . ....... 65 7.4 BehaviourofthePTP............................ 82 7.4.1 Low conductance pore . 82 7.4.2 High conductance pore . 85 8. DISCUSSION................................... 89 Appendices: A. PARTIALDIAGRAMS.............................. 91 ix B. UNSIMPLIFIEDTERMSINRATEEXPRESSIONS . 92 C. MODELPARAMETERS.............................100 C.1 Thermodynamicconstants . .100 C.2 ConversionConstants . .100 C.3 Compartmentalization parameters . 103 C.4 Metabolicparameters. .103 C.5 Rateconstants(ProtonPump) . .103 C.6 Rateconstants(ATPase) . .104 C.7 Electroneutralweakacidparameters . 104 C.8 Permiability transistion pore parameters . 105 C.9 IP3receptorandleakageparameters . 105 C.10SERCApumpparameters . .106 C.11Inputs....................................106 D. MODELEQUATIONS ..............................107 D.1 Compartmental equations . 108 D.2 Nucleotideconservation . 109 D.3 Cytosolic components . 110 D.4 Mitochondrial components . 111 D.5 Endoplasmic Reticulum components . 113 D.6 DifferentialEquations . 114 D.7 Initialconditions ..............................115 Bibliography ......................................116 x LIST OF FIGURES Figure Page 2.1 Components of the MCICR model ( IP3R = IP3 Receptor, SERCA = SERCA Pump, PTP = Permeability Transition Pore, UNI = Calcium uniporter, NaCaE = Sodium Calcium exchanger, ETC = Electron transport Chain, F0F1 = F0-F1 ATPase)............................ 6 2.2 Kinetic diagram of Adenine Nucleotide Transporter . ......... 11 2.3 Allosteric diagram of Calcium Uniporter . ..... 12 2.4 Kinetic diagram of Sodium-Calcium exchanger . ..... 13 3.1 Kinetic diagram of hypothetical proton pump . ...... 21 3.2 Possible cycles in the six-state kinetic diagram . .......... 22 3.3 Kinetic diagram of hypothetical F0-F1 pump................. 24 3.4 Surface and phase boundary potentials of inner mitochondrial membrane . 36 4.1 Three state permeability transition pore . ....... 52 7.1 Comparison of pH dependent Jhres flux with that of Magnus and Keizer . 61 7.2 Comparison of pH dependent Jhres flux with that of Magnus and Keizer . 62 7.3 Comparison of pH dependent Jhf1 flux with that of Magnus and Keizer . 62 7.4 Comparison of pH dependent Jhf1 flux with that of Magnus and Keizer . 63 xi 7.5 Comparison of pH dependent Jo flux with that of Magnus and Keizer . 63 7.6 Comparison of pH dependent Jo flux with that of Magnus and Keizer . 64 7.7 Comparison of pH dependent Jpf1 flux with that of Magnus and Keizer . 64 7.8 Comparison of pH dependent Jpf1 flux with that of Magnus and Keizer . 65 7.9 Jhres in simplified and unsimplified forms . 66 7.10 Jhres in simplified and unsimplified forms . 67 7.11 Jhres in simplified and unsimplified forms . 68 7.12 Jo in simplified and unsimplified forms . 69 7.13 Jo in simplified and unsimplified forms . 70 7.14 Jo in simplified and unsimplified forms . 71 7.15 Jhf1 in simplified and unsimplified forms . 72 7.16 Jhf1 in simplified and unsimplified forms . 73 7.17 Jhf1 in simplified and unsimplified forms . 74 7.18 Jpf1 in simplified and unsimplified forms . 75 7.19 Jpf1 in simplified and unsimplified forms . 76 7.20 Jpf1 in simplified and unsimplified forms . 77 7.21 Change in mitochondrial pH after a cyptoplasmic calcium pulse at t=250 . 78 7.22 Increase in proton pumping by ETC in response to elevated matrix calcium 79 7.23 Elevated baseline cytoplasmic calcium (without ER) . ......... 79 7.24 Elevated baseline mitochondrial calcium (without ER) . .......... 80 7.25 Mitochondrial calcium response in presence of ER . ........ 80 xii 7.26 Mitochondrial pH response in presence of ER . ...... 81 7.27 CalciumuptakebyER ............................ 81 7.28 Response of the PTP to fast cytoplasmic calcium pluses in the presence of theEndoplasmicReticulum. 83 7.29 Response of the PTP to fast cytoplasmic calcium pluses in the presence of theEndoplasmicReticulum. 84 7.30 Response
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