title: Barth Syndrome: From Mitochondrial Dysfunctions Associated with Aberrant Production of Reactive Oxygen Species to Pluripotent Stem Cell Studies.
abstract: Mutations in the gene encoding the enzyme tafazzin, TAZ, cause Barth syndrome (BTHS). Individuals with this X-linked multisystem disorder present cardiomyopathy (CM) (often dilated), skeletal muscle weakness, neutropenia, growth retardation, and 3-methylglutaconic aciduria. Biopsies of the heart, liver and skeletal muscle of patients have revealed mitochondrial malformations and dysfunctions. It is the purpose of this review to summarize recent results of studies on various animal or cell models of Barth syndrome, which have characterized biochemically the strong cellular defects associated with TAZ mutations. Tafazzin is a mitochondrial phospholipidlysophospholipid transacylase that shuttles acyl groups between phospholipids and regulates the remodeling of cardiolipin (CL), a unique inner mitochondrial membrane phospholipid dimer consisting of two phosphatidyl residues linked by a glycerol bridge. After their biosynthesis, the acyl chains of CLs may be modified in remodeling processes involving up to three different enzymes. Their characteristic acyl chain composition depends on the function of tafazzin, although the enzyme itself surprisingly lacks acyl specificity. CLs are crucial for correct mitochondrial structure and function. In addition to their function in the basic mitochondrial function of ATP production, CLs play essential roles in cardiac function, apoptosis, autophagy, cell cycle regulation and Fe-S cluster biosynthesis. Recent developments in tafazzin research have provided strong insights into the link between mitochondrial dysfunction and the production of reactive oxygen species (ROS). An important tool has been the generation of BTHS-specific induced pluripotent stem cells (iPSCs) from BTHS patients. In a complementary approach, disease-specific mutations have been introduced into wild-type iPSC lines enabling direct comparison with isogenic controls. iPSC-derived cardiomyocytes were then characterized using biochemical and classical bioenergetic approaches. The cells are tested in a "heart-on-chip" assay to model the pathophysiology in vitro, to characterize the underlying mechanism of BTHS deriving from TAZ mutations, mitochondrial deficiencies and ROS production and leading to tissue defects, and to evaluate potential therapies with the use of mitochondrially targeted antioxidants.
authors.affiliation: INSERM U 1124 "Toxicologie, Pharmacologie et Signalisation Cellulaire" and "FR 3567" CNRS Chimie, Toxicologie, Signalisation Cellulaire et Cibles Thérapeutiques, Université Paris Descartes - Centre Universitaire des Saints-PèresParis, France; Division of Molecular Medicine, Ruđer Bošković InstituteZagreb, Croatia.
authors.forename: Ana
authors.initials: A
authors.lastname: Saric
authors.affiliation: INSERM U 1124 "Toxicologie, Pharmacologie et Signalisation Cellulaire" and "FR 3567" CNRS Chimie, Toxicologie, Signalisation Cellulaire et Cibles Thérapeutiques, Université Paris Descartes - Centre Universitaire des Saints-Pères Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Andreau
authors.affiliation: INSERM U 1124 "Toxicologie, Pharmacologie et Signalisation Cellulaire" and "FR 3567" CNRS Chimie, Toxicologie, Signalisation Cellulaire et Cibles Thérapeutiques, Université Paris Descartes - Centre Universitaire des Saints-Pères Paris, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Armand
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University Slagelse, Denmark.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Møller
authors.affiliation: INSERM U 1124 "Toxicologie, Pharmacologie et Signalisation Cellulaire" and "FR 3567" CNRS Chimie, Toxicologie, Signalisation Cellulaire et Cibles Thérapeutiques, Université Paris Descartes - Centre Universitaire des Saints-Pères Paris, France.
authors.forename: Patrice X
authors.initials: PX
authors.lastname: Petit
keywords: barth syndrome; cardiolipin; cellular models; mitochondria; mitochondrially targeted antioxidant; stem cells; tafazzin
references.citation: Mitochondrion. 2009 Apr;9(2):86-95
references.pmid: 19114128
references.citation: Hum Gene Ther. 2011 Jul;22(7):865-71
references.pmid: 21091282
references.citation: J Lipid Res. 2006 Jun;47(6):1140-5
references.pmid: 16547353
references.citation: Orphanet J Rare Dis. 2013 Feb 12;8:23
references.pmid: 23398819
references.citation: J Biol Chem. 2004 Oct 22;279(43):44394-9
references.pmid: 15304507
references.citation: Prog Lipid Res. 2013 Oct;52(4):590-614
references.pmid: 24007978
references.citation: Nat Chem. 2014 Jun;6(6):542-52
references.pmid: 24848241
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11860-5
references.pmid: 21730175
references.citation: Biochim Biophys Acta. 2009 Oct;1788(10):2080-3
references.pmid: 19413994
references.citation: FEBS Lett. 1993 Sep 6;330(1):71-6
references.pmid: 8370463
references.citation: Circ J. 2014;78(4):784-94
references.pmid: 24632794
references.citation: J Lipid Res. 2005 Jun;46(6):1182-95
references.pmid: 15805542
references.citation: J Biol Chem. 2013 Jan 18;288(3):1696-705
references.pmid: 23192348
references.citation: Eur J Pediatr. 2008 Aug;167(8):941-4
references.pmid: 17846786
references.citation: EMBO J. 2010 Jun 16;29(12 ):1976-87
references.pmid: 20485265
references.citation: Mol Genet Metab. 2012 May;106(1):115-20
references.pmid: 22410210
references.citation: J Pharmacol Toxicol Methods. 2012 May-Jun;65(3):126-35
references.pmid: 22521339
references.citation: J Am Heart Assoc. 2012 Apr;1(2):null
references.pmid: 23130124
references.citation: Eur Heart J. 2014 Apr;35(16):1078-87
references.pmid: 23470493
references.citation: Curr Cardiol Rep. 2013 Jun;15(6):369
references.pmid: 23666883
references.citation: Lab Chip. 2011 Dec 21;11(24):4165-73
references.pmid: 22072288
references.citation: J Biol Chem. 1990 Nov 5;265(31):18797-802
references.pmid: 2172233
references.citation: Ann Neurol. 2003 Jan;53(1):121-3
references.pmid: 12509856
references.citation: Pediatrics. 2006 Aug;118(2):e337-46
references.pmid: 16847078
references.citation: PLoS One. 2014 Nov 25;9(11):e113680
references.pmid: 25422939
references.citation: J Proteomics. 2011 Oct 19;74(11):2228-42
references.pmid: 21601020
references.citation: Lab Invest. 2002 Mar;82(3):335-44
references.pmid: 11896212
references.citation: PLoS One. 2012;7(11):e48628
references.pmid: 23152787
references.citation: J Biol Chem. 1996 Jan 12;271(2):789-95
references.pmid: 8557688
references.citation: J Pediatr. 1991 Nov;119(5):738-47
references.pmid: 1719174
references.citation: Am J Med Genet A. 2012 Nov;158A(11):2726-32
references.pmid: 23045169
references.citation: J Cell Biol. 2008 Nov 17;183(4):681-96
references.pmid: 19001123
references.citation: Am J Med Genet. 1993 Feb 1;45(3):327-34
references.pmid: 8434619
references.citation: J Biol Chem. 2003 Apr 11;278(15):12716-21
references.pmid: 12569106
references.citation: J Clin Invest. 2013 Mar;123(3):951-7
references.pmid: 23454757
references.citation: Mol Ther. 2011 Mar;19(3):584-93
references.pmid: 21119622
references.citation: Integr Comp Biol. 2010 Nov;50(5):869-79
references.pmid: 21558246
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9770-5
references.pmid: 23716679
references.citation: Biochim Biophys Acta. 1990 Jul 25;1018(2-3):229-33
references.pmid: 2203472
references.citation: Cardiovasc Res. 2004 Nov 1;64(2):198-207
references.pmid: 15485678
references.citation: FEBS Lett. 2006 Oct 9;580(23):5450-5
references.pmid: 16973164
references.citation: J Cell Biol. 2006 Aug 28;174(5):631-7
references.pmid: 16943180
references.citation: J Bacteriol. 1986 Mar;165(3):901-10
references.pmid: 3005242
references.citation: Nat Genet. 1996 Apr;12(4):385-9
references.pmid: 8630491
references.citation: Nat Clin Pract Cardiovasc Med. 2007 Feb;4 Suppl 1:S60-7
references.pmid: 17230217
references.citation: Chem Phys Lipids. 2014 Apr;179:11-6
references.pmid: 24144810
references.citation: EMBO Mol Med. 2012 Mar;4(3):180-91
references.pmid: 22174035
references.citation: Blood. 2004 May 15;103(10):3915-23
references.pmid: 14764526
references.citation: Cell Mol Life Sci. 2008 Aug;65(16):2493-506
references.pmid: 18425414
references.citation: Mol Genet Metab. 2012 Nov;107(3):428-32
references.pmid: 23031367
references.citation: J Physiol. 2006 Jul 1;574(Pt 1):33-9
references.pmid: 16709637
references.citation: Prenat Diagn. 2010 Oct;30(10 ):970-6
references.pmid: 20812380
references.citation: J Mol Cell Cardiol. 1995 Mar;27(3):849-56
references.pmid: 7602601
references.citation: Chem Phys Lipids. 2014 Apr;179:64-9
references.pmid: 24300280
references.citation: J Neurosci Res. 2014 Feb;92(2):218-31
references.pmid: 24273069
references.citation: J Inherit Metab Dis. 1996;19(2):157-60
references.pmid: 8739954
references.citation: J Pediatr. 1999 Sep;135(3):273-6
references.pmid: 10484787
references.citation: JAMA. 2013 Nov 20;310(19):2039-40
references.pmid: 24240927
references.citation: Mol Genet Metab. 2014 Jan;111(1):26-32
references.pmid: 24342716
references.citation: Exp Gerontol. 2010 Aug;45(7-8):466-72
references.pmid: 20064600
references.citation: J Biol Chem. 2011 Jan 14;286(2):899-908
references.pmid: 21068380
references.citation: PLoS One. 2009;4(4):e5329
references.pmid: 19390630
references.citation: Am J Med Genet A. 2004 May 1;126A(4):349-54
references.pmid: 15098233
references.citation: Curr Opin Cardiol. 2010 May;25(3):222-8
references.pmid: 20124997
references.citation: J Cell Biol. 2008 Dec 29;183(7):1213-21
references.pmid: 19114592
references.citation: Am J Pathol. 2013 Sep;183(3):720-34
references.pmid: 23871585
references.citation: J Biol Chem. 1993 Jan 5;268(1):74-9
references.pmid: 8380172
references.citation: Prog Lipid Res. 2000 May;39(3):257-88
references.pmid: 10799718
references.citation: Autophagy. 2014 Feb;10(2):376-8
references.pmid: 24351649
references.citation: J Biol Chem. 2002 Nov 15;277(46):43553-6
references.pmid: 12364341
references.citation: Nat Chem Biol. 2012 Oct;8(10):862-9
references.pmid: 22941046
references.citation: Mol Biol Cell. 2005 Nov;16(11):5202-14
references.pmid: 16135531
references.citation: Chem Phys Lipids. 2005 Dec;138(1-2):38-49
references.pmid: 16226238
references.citation: Anal Chem. 2008 Jul 1;80(13):5051-8
references.pmid: 18510346
references.citation: J Cell Biol. 2006 Jul 31;174(3):379-90
references.pmid: 16880272
references.citation: Mol Biol Cell. 2013 Jun;24(12):2008-20
references.pmid: 23637464
references.citation: Cell Cycle. 2011 Dec 1;10(23):4032-8
references.pmid: 22101267
references.citation: Pediatrics. 1979 Jul;64(1):24-9
references.pmid: 572031
references.citation: Clin Chim Acta. 1976 Sep 6;71(2):349-51
references.pmid: 963901
references.citation: Ann N Y Acad Sci. 2008 Oct;1142:133-58
references.pmid: 18990125
references.citation: Circ Res. 2006 Jul 21;99(2):201-8
references.pmid: 16794186
references.citation: Pediatr Cardiol. 2012 Dec;33(8):1430-4
references.pmid: 22427193
references.citation: J Biol Chem. 2009 Oct 16;284(42):29230-9
references.pmid: 19700766
references.citation: Int J Obes (Lond). 2008 Sep;32 Suppl 4:S7-12
references.pmid: 18719601
references.citation: J Cell Biol. 2011 Feb 7;192(3):447-62
references.pmid: 21300850
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12017-22
references.pmid: 17609368
references.citation: Nat Med. 2013 Sep;19(9):1111-3
references.pmid: 23913125
references.citation: Dev Cell. 2011 Sep 13;21(3):469-78
references.pmid: 21920313
references.citation: Biochim Biophys Acta. 2009 Apr;1791(4):314-20
references.pmid: 19416660
references.citation: J Biol Chem. 2005 Jun 3;280(22):21295-312
references.pmid: 15788391
references.citation: Biochim Biophys Acta. 1990 Jan 29;1021(2):217-26
references.pmid: 2154259
references.citation: Curr Cardiol Rep. 2012 Apr;14(2):208-16
references.pmid: 22327929
references.citation: Biochim Biophys Acta. 1985 Jun 12;822(1):1-42
references.pmid: 2408671
references.citation: J Histochem Cytochem. 2015 May;63(5):301-11
references.pmid: 25673287
references.citation: Am J Physiol Cell Physiol. 2009 May;296(5):C1185-94
references.pmid: 19295176
references.citation: Eukaryot Cell. 2013 Dec;12(12):1600-8
references.pmid: 24078306
references.citation: Mol Microbiol. 2008 May;68(4):1061-72
references.pmid: 18430085
references.citation: J Cell Biol. 2009 Sep 21;186(6):793-803
references.pmid: 19752025
references.citation: Meta Gene. 2015 Apr 22;4:92-106
references.pmid: 25941633
references.citation: Nat Biotechnol. 2013 Jan;31(1):20-3
references.pmid: 23302926
references.citation: Cell Death Differ. 2007 Mar;14(3):597-606
references.pmid: 16888643
references.citation: Carcinogenesis. 2005 Nov;26(11):1914-21
references.pmid: 15975958
references.citation: EMBO J. 2000 Nov 1;19(21):5720-8
references.pmid: 11060023
references.citation: Am J Hum Genet. 1998 Nov;63(5):1457-63
references.pmid: 9792874
references.citation: Curr Genet. 1998 Oct;34(4):297-302
references.pmid: 9799363
references.citation: Am J Med Genet C Semin Med Genet. 2013 Aug;163C(3):198-205
references.pmid: 23843353
references.citation: J Lipid Res. 2009 Aug;50(8):1600-8
references.pmid: 19001357
references.citation: Am J Hum Genet. 1994 Sep;55(3):437-46
references.pmid: 8079988
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: J Biol Chem. 1998 Apr 17;273(16):9829-36
references.pmid: 9545322
references.citation: Am J Physiol Heart Circ Physiol. 2010 Jul;299(1):H210-6
references.pmid: 20348225
references.citation: Mol Cell Biol. 2012 Nov;32(21):4493-504
references.pmid: 22949503
references.citation: J Am Coll Cardiol. 2012 Sep 11;60(11):990-1000
references.pmid: 22749309
references.citation: Biochim Biophys Acta. 2013 Aug;1832(8):1194-206
references.pmid: 23523468
references.citation: Hum Genet. 1987 Mar;75(3):286-90
references.pmid: 3030927
references.citation: Front Genet. 2015 Feb 03;6:3
references.pmid: 25691889
references.citation: Chem Phys Lipids. 2014 Apr;179:49-56
references.pmid: 24445246
references.citation: Sci Rep. 2013;3:1263
references.pmid: 23405277
references.citation: Pediatr Cardiol. 2005 Sep-Oct;26(5):632-7
references.pmid: 16235007
references.citation: Hum Mol Genet. 2010 Jun 1;19(11):2113-22
references.pmid: 20185555
references.citation: N Engl J Med. 2010 Oct 7;363(15):1397-409
references.pmid: 20660394
references.citation: J Neurol Sci. 1983 Dec;62(1-3):327-55
references.pmid: 6142097
references.citation: Stem Cell Res. 2013 Sep;11(2):806-19
references.pmid: 23792436
references.citation: Science. 2007 Dec 21;318(5858):1917-20
references.pmid: 18029452
references.citation: Nat Neurosci. 2012 Oct;15(10):1407-13
references.pmid: 22922784
references.citation: Biochem J. 2006 Sep 1;398(2):169-76
references.pmid: 16716149
references.citation: Oxid Med Cell Longev. 2014;2014:654198
references.pmid: 25247053
references.citation: World J Cardiol. 2014 Oct 26;6(10):1091-9
references.pmid: 25349653
references.citation: Dis Model Mech. 2013 May;6(3):608-21
references.pmid: 23136396
references.citation: Am J Med Genet A. 2005 May 1;134(4):409-14
references.pmid: 15793838
references.citation: Prog Lipid Res. 2014 Jul;55:1-16
references.pmid: 24769127
references.citation: Mol Cell. 2009 Mar 13;33(5):627-38
references.pmid: 19285945
references.citation: J Cell Biol. 2008 Sep 8;182(5):937-50
references.pmid: 18779372
references.citation: Cell Metab. 2013 May 7;17(5):709-18
references.pmid: 23623749
references.citation: J Lipid Res. 2003 Mar;44(3):560-6
references.pmid: 12562862
references.citation: Biochem J. 2009 Mar 1;418(2):261-75
references.pmid: 19196246
references.citation: Biochim Biophys Acta. 1971 Jun 8;239(1):113-9
references.pmid: 4998839
references.citation: Nat Commun. 2014 May 30;5:3903
references.pmid: 24875164
references.citation: Cell Stem Cell. 2013 Jan 3;12(1):101-13
references.pmid: 23290139
references.citation: J Biol Chem. 2005 Aug 19;280(33):29403-8
references.pmid: 15972817
references.citation: J Biol Chem. 1998 Jun 12;273(24):14933-41
references.pmid: 9614098
references.citation: Biochim Biophys Acta. 2013 Mar;1831(3):582-8
references.pmid: 23200781
references.citation: J Biol Chem. 2003 Dec 19;278(51):51380-5
references.pmid: 14551214
references.citation: Curr Biol. 2009 Dec 29;19(24):2133-9
references.pmid: 19962311
references.citation: Am J Med Genet A. 2007 May 1;143A(9):907-15
references.pmid: 17394203
references.citation: Nat Med. 2014 Jun;20(6):616-23
references.pmid: 24813252
references.citation: Aging (Albany NY). 2013 Jun;5(6):392-3
references.pmid: 23807703
references.citation: Nat Chem Biol. 2012 Oct;8(10):811-2
references.pmid: 22987008
references.citation: Am J Physiol Cell Physiol. 2007 Jan;292(1):C33-44
references.pmid: 16899548
references.citation: Autophagy. 2015 Apr 3;11(4):643-52
references.pmid: 25919711
references.citation: Biochem J. 2005 May 1;387(Pt 3):617-26
references.pmid: 15588229
references.citation: J Biol Chem. 2006 Dec 22;281(51):39217-24
references.pmid: 17082194
references.citation: Am J Hum Genet. 1997 Nov;61(5):1053-8
references.pmid: 9345098
references.citation: Nat Med. 2014 Jun;20(6):585-6
references.pmid: 24901565
references.citation: Science. 2008 Aug 29;321(5893):1218-21
references.pmid: 18669821
references.citation: Lab Invest. 2005 Jun;85(6):823-30
references.pmid: 15806137
references.citation: Nat Methods. 2013 Oct;10(10):957-63
references.pmid: 24076990
references.citation: Biochim Biophys Acta. 2009 Jan;1793(1):212-8
references.pmid: 18725250
references.citation: J Biol Chem. 2004 Jul 30;279(31):32294-300
references.pmid: 15169766
references.citation: Biochem J. 2000 May 1;347 Pt 3:687-91
references.pmid: 10769171
references.citation: J Inherit Metab Dis. 2013 Sep;36(5):741-6
references.pmid: 23109063
references.citation: Mitochondrion. 2015 Mar;21:27-32
references.pmid: 25598000
references.citation: Biochemistry (Mosc). 2008 Dec;73(12):1273-87
references.pmid: 19120014
references.citation: Lab Invest. 2007 Jan;87(1):40-8
references.pmid: 17043667
references.citation: Cell Stem Cell. 2014 Jul 3;15(1):9-11
references.pmid: 24996164
references.citation: Circ Res. 2013 Jan 18;112(2):393-405
references.pmid: 23329794
references.citation: Trends Biochem Sci. 2012 Jan;37(1):32-41
references.pmid: 22014644
references.citation: Curr Opin Hematol. 2009 Jan;16(1):14-9
references.pmid: 19057200
references.citation: Nature. 2009 Aug 13;460(7257):831-8
references.pmid: 19675643
references.citation: Chem Phys Lipids. 2014 Apr;179:25-31
references.pmid: 24184646
references.citation: Circulation. 2001 Mar 6;103(9):1256-63
references.pmid: 11238270
references.citation: Biochem Cell Biol. 2004 Feb;82(1):99-112
references.pmid: 15052331
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 3;109 (1):215-20
references.pmid: 22178754
references.citation: Circulation. 2003 Nov 25;108(21):2672-8
references.pmid: 14623814
references.citation: Hum Mol Genet. 2013 Feb 1;22(3):483-92
references.pmid: 23100323
references.citation: Nat Cell Biol. 2013 Oct;15(10):1197-205
references.pmid: 24036476
references.citation: J Biol Chem. 2003 Oct 31;278(44):43089-94
references.pmid: 12930833
references.citation: Am J Physiol Heart Circ Physiol. 2013 Nov 1;305(9):H1332-43
references.pmid: 23997105
references.citation: Cell Metab. 2014 Jul 1;20(1):158-71
references.pmid: 24856930
references.citation: Methods Enzymol. 2014;546:119-38
references.pmid: 25398338
references.citation: FEBS Lett. 2002 Sep 25;528(1-3):35-9
references.pmid: 12297275
references.citation: Chem Phys Lipids. 2014 Apr;179:3-10
references.pmid: 24333544
references.citation: J Biol Chem. 2001 Feb 16;276(7):4588-96
references.pmid: 11092892
references.citation: Proc Natl Acad Sci U S A. 2012 May 1;109(18):6975-80
references.pmid: 22509026
references.citation: Chem Phys Lipids. 2012 Jul;165(5):512-9
references.pmid: 22465155
references.citation: PLoS One. 2014 Jul 22;9(7):e102796
references.pmid: 25050861
references.citation: Cardiovasc Hematol Disord Drug Targets. 2014;14(2):98-106
references.pmid: 24801725
references.citation: Cell Metab. 2011 Jun 8;13(6):690-700
references.pmid: 21641550
references.citation: J Bioenerg Biomembr. 2016 Apr;48(2):113-23
references.pmid: 25432572
references.citation: Biochim Biophys Acta. 2009 Oct;1788(10):2003-14
references.pmid: 19619503
references.citation: J Mol Biol. 2006 Aug 18;361(3):462-9
references.pmid: 16857210
references.citation: Autophagy. 2013 Nov 1;9(11):1663-76
references.pmid: 23787782