title: A computational model of reactive oxygen species and redox balance in cardiac mitochondria.
abstract: Elevated levels of reactive oxygen species (ROS) play a critical role in cardiac myocyte signaling in both healthy and diseased cells. Mitochondria represent the predominant cellular source of ROS, specifically the activity of complexes I and III. The model presented here explores the modulation of electron transport chain ROS production for state 3 and state 4 respiration and the role of substrates and respiratory inhibitors. Model simulations show that ROS production from complex III increases exponentially with membrane potential (ΔΨm) when in state 4. Complex I ROS release in the model can occur in the presence of NADH and succinate (reverse electron flow), leading to a highly reduced ubiquinone pool, displaying the highest ROS production flux in state 4. In the presence of ample ROS scavenging, total ROS production is moderate in state 3 and increases substantially under state 4 conditions. The ROS production model was extended by combining it with a minimal model of ROS scavenging. When the mitochondrial redox status was oxidized by increasing the proton permeability of the inner mitochondrial membrane, simulations with the combined model show that ROS levels initially decline as production drops off with decreasing ΔΨm and then increase as scavenging capacity is exhausted. Hence, this mechanistic model of ROS production demonstrates how ROS levels are controlled by mitochondrial redox balance.
authors: Institute for Computational Medicine, Baltimore, MD, USA. laura.doyle@jhu.edu
authors: Laura D
authors: LD
authors: Gauthier
authors: Joseph L
authors: JL
authors: Greenstein
authors: Sonia
authors: S
authors: Cortassa
authors: Brian
authors: B
authors: O'Rourke
authors: Raimond L
authors: RL
authors: Winslow
mesh_terms: D019069:Cell Respiration; D003198:Computer Simulation; D045222:Electron Transport Chain Complex Proteins / Q000737:chemistry / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D009206:Myocardium / Q000166:cytology*; D010084:Oxidation-Reduction; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D045222:Electron Transport Chain Complex Proteins; D017382:Reactive Oxygen Species
references: Circulation. 2010 Apr 13;121(14):1606-13
references: 20351235
references: Mol Cell Biochem. 1996 May 24;158(2):133-8
references: 8817475
references: Arch Biochem Biophys. 1985 Mar;237(2):408-14
references: 2983613
references: J Clin Invest. 1971 Jun;50(6):1181-6
references: 4325308
references: J Biol Chem. 2011 May 20;286(20):18056-65
references: 21393237
references: J Bioenerg Biomembr. 1999 Aug;31(4):367-76
references: 10665526
references: Physiol Rev. 2002 Jan;82(1):47-95
references: 11773609
references: J Physiol. 2003 Oct 15;552(Pt 2):335-44
references: 14561818
references: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7607-12
references: 16682634
references: Free Radic Biol Med. 2001 Jun 1;30(11):1191-212
references: 11368918
references: Biophys J. 2010 Sep 8;99(5):1426-36
references: 20816054
references: Adv Exp Med Biol. 2012;748:145-69
references: 22729857
references: J Bioenerg Biomembr. 1998 Feb;30(1):99-107
references: 9623811
references: Biophys J. 2011 Jun 22;100(12):2894-903
references: 21689522
references: Biochim Biophys Acta. 2011 Mar;1807(3):348-58
references: 21211514
references: Proc Natl Acad Sci U S A. 2007 May 8;104(19):7887-92
references: 17470780
references: Biochim Biophys Acta. 2003 Jun 5;1604(2):77-94
references: 12765765
references: Biochim Biophys Acta. 2006 Sep-Oct;1757(9-10):1096-109
references: 16780790
references: Biochim Biophys Acta. 1992 Apr 10;1100(1):67-74
references: 1314666
references: Biophys J. 2003 Apr;84(4):2734-55
references: 12668482
references: J Biol Chem. 2008 Oct 24;283(43):29292-300
references: 18687689
references: PLoS Comput Biol. 2011 Mar;7(3):e1001115
references: 21483483
references: Biochem J. 1985 Jan 15;225(2):399-405
references: 2983670
references: Mol Cell Biochem. 1998 Jul;184(1-2):21-33
references: 9746310
references: J Biol Chem. 2006 Oct 27;281(43):32724-7
references: 16950771
references: Biochemistry. 1994 Aug 23;33(33):10069-75
references: 8060976
references: Biochem Biophys Res Commun. 2001 Mar 2;281(3):645-50
references: 11237706
references: Biochim Biophys Acta. 2006 May-Jun;1757(5-6):553-61
references: 16678117
references: Mitochondrion. 2011 Sep;11(5):700-6
references: 21703366
references: J Biol Chem. 2009 Jul 17;284(29):19203-10
references: 19478336
references: Mol Biol (Mosk). 2001 Nov-Dec;35(6):1095-104
references: 11771135
references: Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):865-77
references: 20175987
references: PLoS Comput Biol. 2012;8(9):e1002700
references: 23028295
references: Circ Res. 2009 Jan 2;104(1):79-86
references: 19038865
references: J Biol Chem. 2004 Nov 19;279(47):49064-73
references: 15317809
references: PLoS Comput Biol. 2009 Dec;5(12):e1000619
references: 20041200
references: Biophys J. 2006 Aug 15;91(4):1564-89
references: 16679365
references: Biophys J. 2002 Oct;83(4):1797-808
references: 12324402
references: Biochem J. 2002 Dec 1;368(Pt 2):545-53
references: 12180906
references: FEBS Lett. 1997 Oct 13;416(1):15-8
references: 9369223
references: Am J Physiol. 1993 Apr;264(4 Pt 1):C961-7
references: 8386454
references: Circ Res. 1999 Aug 20;85(4):357-63
references: 10455064
references: FEBS Lett. 2001 Sep 21;505(3):364-8
references: 11576529
references: Cell Metab. 2005 Jun;1(6):401-8
references: 16054089
references: J Biol Chem. 1997 Jul 11;272(28):17594-604
references: 9211907
references: Biochem J. 2004 Sep 1;382(Pt 2):511-7
references: 15175007
references: Circulation. 2002 Jul 16;106(3):362-7
references: 12119254
references: J Biol Chem. 2002 Nov 22;277(47):44784-90
references: 12237311
references: Eur J Biochem. 1990 Mar 10;188(2):313-9
references: 2156698
references: J Membr Biol. 1982;70(1):1-14
references: 6226798
references: Am J Physiol. 1997 Aug;273(2 Pt 1):C717-33
references: 9277370
references: J Biol Chem. 2008 Aug 1;283(31):21649-54
references: 18522938
references: Biochem J. 2000 Jul 15;349(Pt 2):519-26
references: 10880351
references: Circ Res. 2008 Aug 1;103(3):279-88
references: 18599868
references: PLoS Biol. 2011 Aug;9(8):e1001129
references: 21886481
references: Cardiovasc Res. 2006 Jul 15;71(2):208-15
references: 16631149
references: Biochem J. 1980 Nov 1;191(2):421-7
references: 6263247
references: Biochem J. 1980 Apr 15;188(1):31-7
references: 7406888
references: Biochim Biophys Acta. 2011 Oct;1807(10):1364-9
references: 21565159
references: Biophys J. 2004 Sep;87(3):2060-73
references: 15345581
references: FASEB J. 2007 Apr;21(4):1099-106
references: 17264172
references: FASEB J. 1995 May;9(8):651-8
references: 7768357
references: J Biol Chem. 2003 Feb 21;278(8):5557-63
references: 12482755
references: BMC Bioinformatics. 2009 Aug 04;10:238
references: 19653903
references: Biochim Biophys Acta. 2007 Jul;1767(7):883-7
references: 17560537
references: J Mol Cell Cardiol. 1997 Jan;29(1):207-16
references: 9040035
references: Am J Physiol Cell Physiol. 2007 Apr;292(4):C1221-39
references: 17035300
references: J Biol Chem. 2004 Sep 17;279(38):39414-20
references: 15262965
references: J Biol Chem. 1994 Jun 17;269(24):16638-42
references: 7515881
references: Biochemistry. 2008 Nov 25;47(47):12365-70
references: 18956890
references: Biophys J. 2009 Oct 7;97(7):1843-52
references: 19804714
references: J Gen Physiol. 2012 Jun;139(6):479-91
references: 22585969
references: Trends Pharmacol Sci. 2006 Dec;27(12):639-45
references: 17056127
references: J Bioenerg Biomembr. 2008 Oct;40(5):493-9
references: 18975063
references: Biochim Biophys Acta. 1969 Jun 24;180(2):227-36
references: 4307585
references: J Clin Invest. 2005 Mar;115(3):500-8
references: 15765131
references: Nature. 2011 Aug 07;476(7361):414-20
references: 21822288
references: J Bioenerg Biomembr. 2009 Aug;41(4):387-93
references: 19821037
references: Biophys J. 2012 Mar 7;102(5):1194-203
references: 22404942