title: Dynamic simulation of cardiolipin remodeling: greasing the wheels for an interpretative approach to lipidomics.
abstract: Cardiolipin is a class of mitochondrial specific phospholipid, which is intricately involved in mitochondrial functionality. Differences in cardiolipin species exist in a variety of tissues and diseases. It has been demonstrated that the cardiolipin profile is a key modulator of the functions of many mitochondrial proteins. However, the chemical mechanism(s) leading to normal and/or pathological distribution of cardiolipin species remain elusive. Herein, we describe a novel approach for investigating the molecular mechanism of cardiolipin remodeling through a dynamic simulation. This approach applied data from shotgun lipidomic analyses of the heart, liver, brain, and lung mitochondrial lipidomes to model cardiolipin remodeling, including relative content, regiospecificity, and isomeric composition of cardiolipin species. Generated cardiolipin profiles were nearly identical to those determined by shotgun lipidomics. Importantly, the simulated isomeric compositions of cardiolipin species were further substantiated through product ion analysis. Finally, unique enzymatic activities involved in cardiolipin remodeling were assessed from the parameters used in the dynamic simulation of cardiolipin profiles. Collectively, we described, verified, and demonstrated a novel approach by integrating both lipidomic analysis and dynamic simulation to study cardiolipin biology. We believe this study provides a foundation to investigate cardiolipin metabolism and bioenergetic homeostasis in normal and disease states.
authors.affiliation: Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kiebish
authors.forename: Rob
authors.initials: R
authors.lastname: Bell
authors.forename: Kui
authors.initials: K
authors.lastname: Yang
authors.forename: Toan
authors.initials: T
authors.lastname: Phan
authors.forename: Zhongdan
authors.initials: Z
authors.lastname: Zhao
authors.forename: William
authors.initials: W
authors.lastname: Ames
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Seyfried
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Chuang
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
mesh_terms: D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D002308:Cardiolipins / Q000737:chemistry* / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009928:Organ Specificity; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D002308:Cardiolipins; D000217:Acyltransferases
references.citation: Anal Chem. 2009 Jun 1;81(11):4356-68
references.pmid: 19408941
references.citation: Biochim Biophys Acta. 1989 Apr 3;1002(2):261-3
references.pmid: 2930773
references.citation: Lipids. 2008 Oct;43(10):951-9
references.pmid: 18560917
references.citation: PLoS One. 2007 Dec 26;2(12):e1368
references.pmid: 18159251
references.citation: J Biol Chem. 2006 Dec 22;281(51):39217-24
references.pmid: 17082194
references.citation: J Lipid Res. 2008 Aug;49(8):1607-20
references.pmid: 18077827
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Sep 15;877(26):2847-54
references.pmid: 19131280
references.citation: J Mol Endocrinol. 2009 Mar;42(3):185-90
references.pmid: 19060177
references.citation: J Biol Chem. 2004 Jul 23;279(30):31727-34
references.pmid: 15152008
references.citation: Anal Biochem. 2004 Jul 15;330(2):317-31
references.pmid: 15203339
references.citation: Biochim Biophys Acta. 2000 Jan 3;1483(1):1-14
references.pmid: 10601692
references.citation: Mol Microbiol. 2004 Jan;51(1):149-58
references.pmid: 14651618
references.citation: J Lipid Res. 2008 Dec;49(12):2545-56
references.pmid: 18703489
references.citation: Methods Enzymol. 2007;432:247-73
references.pmid: 17954221
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2089-90
references.pmid: 19211786
references.citation: Anal Chem. 2008 Oct 1;80(19):7576-85
references.pmid: 18767869
references.citation: Ultramicroscopy. 2007 Oct;107(10-11):943-7
references.pmid: 17570594
references.citation: Biophys J. 2009 Jun 3;96(11):4542-51
references.pmid: 19486676
references.citation: Mech Ageing Dev. 1984 Mar;24(3):343-51
references.pmid: 6717095
references.citation: Biochim Biophys Acta. 2009 Apr;1791(4):314-20
references.pmid: 19416660
references.citation: J Comp Physiol B. 2006 Feb;176(2):93-105
references.pmid: 16408229
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2337-41
references.pmid: 19164547
references.citation: J Phys Chem B. 2009 Mar 19;113(11):3413-22
references.pmid: 19228006
references.citation: Biochim Biophys Acta. 2006 Feb;1758(2):213-21
references.pmid: 16556434
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Sep 15;877(26):2855-62
references.pmid: 19200789
references.citation: Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E647-53
references.pmid: 19106248
references.citation: ASN Neuro. 2009 May 27;1(3):
references.pmid: 19570033
references.citation: J Mol Recognit. 2007 Nov-Dec;20(6):546-53
references.pmid: 17907278
references.citation: J Biol Chem. 2009 Oct 16;284(42):29230-9
references.pmid: 19700766
references.citation: Expert Rev Proteomics. 2005 Apr;2(2):253-64
references.pmid: 15892569
references.citation: J Biol Chem. 2003 Dec 19;278(51):51380-5
references.pmid: 14551214
references.citation: J Biol Chem. 2003 Oct 31;278(44):43089-94
references.pmid: 12930833
references.citation: J Lipid Res. 2003 Jun;44(6):1071-9
references.pmid: 12671038
references.citation: Cell Mol Life Sci. 2008 Aug;65(16):2493-506
references.pmid: 18425414
references.citation: Biochim Biophys Acta. 2007 Mar;1771(3):432-41
references.pmid: 16904369
references.citation: Rapid Commun Mass Spectrom. 2008 Jul;22(13):2115-24
references.pmid: 18523984
references.citation: J Lipid Res. 2005 Jun;46(6):1182-95
references.pmid: 15805542
references.citation: J Gerontol A Biol Sci Med Sci. 2002 Jan;57(1):B22-8
references.pmid: 11773203
references.citation: J Lipid Res. 2010 Jun;51(6):1599-609
references.pmid: 20124011
references.citation: Biochemistry. 2007 May 29;46(21):6417-28
references.pmid: 17487985
references.citation: J Phys Chem B. 2007 Jun 28;111(25):7194-200
references.pmid: 17542632
references.citation: Am J Physiol Cell Physiol. 2007 Jan;292(1):C33-44
references.pmid: 16899548
references.citation: Mitochondrion. 2009 Apr;9(2):86-95
references.pmid: 19114128
references.citation: FEBS Lett. 2006 Oct 9;580(23):5450-5
references.pmid: 16973164
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10977-81
references.pmid: 8248200
references.citation: J Neurochem. 2007 Apr;101(1):57-76
references.pmid: 17241120
references.citation: J Phys Chem B. 2008 Sep 18;112(37):11655-63
references.pmid: 18712912
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Sep 15;877(26):2924-36
references.pmid: 19201264
references.citation: J Biol Chem. 2000 Jul 21;275(29):22387-94
references.pmid: 10777514
references.citation: Biochim Biophys Acta. 1992 Mar 26;1113(1):71-133
references.pmid: 1550861
references.citation: Mass Spectrom Rev. 2005 May-Jun;24(3):367-412
references.pmid: 15389848
references.citation: Prog Lipid Res. 2006 Mar;45(2):91-101
references.pmid: 16442164
references.citation: J Neurochem. 2008 Jul;106(1):299-312
references.pmid: 18373617
references.citation: J Biol Chem. 2009 Oct 30;284(44):30360-71
references.pmid: 19737925
references.citation: J Biol Chem. 1960 Aug;235:2233-7
references.pmid: 14413818
references.citation: Biochemistry. 2008 May 27;47(21):5869-80
references.pmid: 18454555
references.citation: Methods Mol Biol. 2009;580:339-68
references.pmid: 19784609
references.citation: Mol Pharmacol. 2004 Apr;65(4):813-21
references.pmid: 15044609
references.citation: Anal Chem. 2007 Sep 1;79(17):6629-40
references.pmid: 17665876
references.citation: Biochim Biophys Acta. 2009 Oct;1788(10):2003-14
references.pmid: 19619503
references.citation: Chem Phys Lipids. 2005 Dec;138(1-2):38-49
references.pmid: 16226238
references.citation: J Lipid Res. 2006 Apr;47(4):864-79
references.pmid: 16449763
references.citation: Biochim Biophys Acta. 2009 Apr;1791(4):321-5
references.pmid: 19416646