title: Deacylation on the matrix side of the mitochondrial inner membrane regulates cardiolipin remodeling.
abstract: The mitochondrial-specific lipid cardiolipin (CL) is required for numerous processes therein. After its synthesis on the matrix-facing leaflet of the inner membrane (IM), CL undergoes acyl chain remodeling to achieve its final form. In yeast, this process is completed by the transacylase tafazzin, which associates with intermembrane space (IMS)-facing membrane leaflets. Mutations in TAZ1 result in the X-linked cardiomyopathy Barth syndrome. Amazingly, despite this clear pathophysiological association, the physiological importance of CL remodeling is unresolved. In this paper, we show that the lipase initiating CL remodeling, Cld1p, is associated with the matrix-facing leaflet of the mitochondrial IM. Thus monolysocardiolipin generated by Cld1p must be transported to IMS-facing membrane leaflets to gain access to tafazzin, identifying a previously unknown step required for CL remodeling. Additionally, we show that Cld1p is the major site of regulation in CL remodeling; and that, like CL biosynthesis, CL remodeling is augmented in growth conditions requiring mitochondrially produced energy. However, unlike CL biosynthesis, dissipation of the mitochondrial membrane potential stimulates CL remodeling, identifying a novel feedback mechanism linking CL remodeling to oxidative phosphorylation capacity.
authors: Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205-2185, USA.
authors: Matthew G
authors: MG
authors: Baile
authors: Kevin
authors: K
authors: Whited
authors: Steven M
authors: SM
authors: Claypool
mesh_terms: D000215:Acylation; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002308:Cardiolipins / Q000378:metabolism*; D015151:Immunoblotting; D007476:Ionophores / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010740:Phospholipases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014634:Valinomycin / Q000494:pharmacology
chemical_list: D002308:Cardiolipins; D007476:Ionophores; D008246:Lysophospholipids; D029701:Saccharomyces cerevisiae Proteins; C067188:monolysocardiolipin; D014634:Valinomycin; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000217:Acyltransferases; C481660:Taz1 protein, S cerevisiae; C585646:CLD1 protein, S cerevisiae; D010740:Phospholipases
references: Biophys J. 2011 May 4;100(9):2184-92
references: 21539786
references: Cell Metab. 2011 Jun 8;13(6):690-700
references: 21641550
references: Curr Protein Pept Sci. 2000 Sep;1(2):209-35
references: 12369917
references: J Biol Chem. 1981 Feb 25;256(4):1874-80
references: 6257690
references: J Biol Chem. 1990 Nov 15;265(32):19434-40
references: 2147180
references: J Biol Chem. 2005 Aug 19;280(33):29403-8
references: 15972817
references: FEBS Lett. 1998 Jan 2;421(1):15-8
references: 9462830
references: Biochemistry. 2008 May 27;47(21):5869-80
references: 18454555
references: Free Radic Biol Med. 2006 Jul 15;41(2):238-46
references: 16814104
references: EMBO J. 2010 Jun 16;29(12):1976-87
references: 20485265
references: Cell. 2006 Jul 14;126(1):177-89
references: 16839885
references: Biochem Biophys Res Commun. 2003 Jan 3;300(1):65-74
references: 12480522
references: J Cell Biol. 2008 Sep 8;182(5):937-50
references: 18779372
references: J Biol Chem. 2004 Jul 30;279(31):32294-300
references: 15169766
references: Mol Microbiol. 2004 Jan;51(1):149-58
references: 14651618
references: J Biol Chem. 2009 Apr 24;284(17):11572-8
references: 19244244
references: Yeast. 1994 Dec;10(13):1793-808
references: 7747518
references: Protein Pept Lett. 2009;16(10):1137-48
references: 19508187
references: Science. 2012 Nov 9;338(6108):815-8
references: 23042293
references: Structure. 1997 Dec 15;5(12):1571-84
references: 9438866
references: J Biol Chem. 2004 Feb 6;279(6):3956-79
references: 14597615
references: EMBO J. 2008 Jan 23;27(2):433-46
references: 18200046
references: Protein Sci. 2002 Sep;11(9):2184-95
references: 12192074
references: J Biol Chem. 2001 Oct 12;276(41):38061-7
references: 11500520
references: J Cell Biol. 2010 Nov 29;191(5):933-42
references: 21115803
references: J Biochem. 2003 Apr;133(4):397-403
references: 12761285
references: J Biol Chem. 2004 Oct 8;279(41):42612-8
references: 15292198
references: Electrophoresis. 1997 Dec;18(15):2714-23
references: 9504803
references: Front Biosci (Landmark Ed). 2013 Jan 01;18:241-78
references: 23276920
references: Nature. 2012 Nov 15;491(7424):374-83
references: 23151580
references: Trends Biochem Sci. 2012 Jan;37(1):32-41
references: 22014644
references: J Neurol Sci. 1983 Dec;62(1-3):327-55
references: 6142097
references: Biochim Biophys Acta. 2009 Apr;1791(4):314-20
references: 19416660
references: Biochim Biophys Acta. 2006 May-Jun;1757(5-6):553-61
references: 16678117
references: J Cell Biol. 2009 Sep 21;186(6):793-803
references: 19752025
references: Hum Mol Genet. 2010 Jun 1;19(11):2113-22
references: 20185555
references: Biochem J. 2000 May 1;347 Pt 3:687-91
references: 10769171
references: Nat Rev Mol Cell Biol. 2008 Feb;9(2):112-24
references: 18216768
references: Biochem Biophys Res Commun. 1980 Apr 29;93(4):1238-46
references: 6249285
references: Nat Cell Biol. 2007 Oct;9(10):1152-9
references: 17828250
references: Lab Invest. 2007 Jan;87(1):40-8
references: 17043667
references: J Cell Biol. 2011 Feb 7;192(3):447-62
references: 21300850
references: J Biol Chem. 1998 May 8;273(19):11638-42
references: 9565583
references: Biochem J. 1997 Jun 1;324 ( Pt 2):627-34
references: 9182727
references: Biochim Biophys Acta. 2012 Sep;1817(9):1588-96
references: 22575443
references: Cell. 2010 Sep 17;142(6):889-901
references: 20850011
references: Mol Biol Cell. 2005 Nov;16(11):5202-14
references: 16135531
references: Cell Metab. 2010 Aug 4;12(2):154-65
references: 20674860
references: J Biol Chem. 2012 Oct 26;287(44):36744-55
references: 22984266
references: Mol Biol Cell. 2008 Dec;19(12):5143-55
references: 18799610
references: EMBO J. 1983;2(7):1105-11
references: 16453466
references: J Biol Chem. 2012 Dec 21;287(52):43961-71
references: 23124206
references: Gene. 1989 Apr 15;77(1):51-9
references: 2744487
references: Mol Microbiol. 2008 May;68(4):1061-72
references: 18430085
references: J Biol Chem. 2003 Dec 19;278(51):51380-5
references: 14551214
references: J Cell Biol. 2008 Nov 17;183(4):681-96
references: 19001123
references: J Neurochem. 2005 Feb;92(4):840-9
references: 15686486
references: J Struct Biol. 2011 Sep;175(3):362-71
references: 21741480
references: J Biol Chem. 1982 Nov 10;257(21):13028-33
references: 6290489
references: Biochim Biophys Acta. 1999 Apr 14;1418(1):61-70
references: 10209211
references: J Am Coll Cardiol. 2003 Dec 3;42(11):1994-9
references: 14662265
references: J Lipid Res. 2005 Jun;46(6):1182-95
references: 15805542
references: J Bioenerg Biomembr. 2008 Oct;40(5):445-56
references: 18843528
references: Yeast. 2006 Mar;23(4):279-91
references: 16544270
references: Eur J Biochem. 1994 Mar 15;220(3):871-9
references: 8143741
references: Cell. 1992 May 29;69(5):809-22
references: 1350514
references: J Biol Chem. 2006 Dec 22;281(51):39217-24
references: 17082194
references: Lipids. 1970 May;5(5):494-6
references: 5483450
references: Prog Lipid Res. 2000 May;39(3):257-88
references: 10799718
references: Nucleic Acids Res. 2003 Jul 1;31(13):3381-5
references: 12824332
references: J Biol Chem. 1955 Nov;217(1):409-27
references: 13271404
references: J Cell Biol. 2006 Jul 31;174(3):379-90
references: 16880272
references: Biochim Biophys Acta. 2013 Aug;1832(8):1194-206
references: 23523468
references: Mitochondrion. 2009 Apr;9(2):86-95
references: 19114128
references: Nat Genet. 1996 Apr;12(4):385-9
references: 8630491
references: Mol Microbiol. 1997 Nov;26(3):481-91
references: 9402019
references: Bioinformatics. 2006 Jan 15;22(2):195-201
references: 16301204
references: FEBS Lett. 2006 Oct 9;580(23):5450-5
references: 16973164
references: Curr Biol. 2009 Dec 29;19(24):2133-9
references: 19962311
references: J Lipid Res. 2011 Jan;52(1):125-35
references: 20858593
references: Biochemistry. 2009 Dec 1;48(47):11185-95
references: 19863062
references: J Biol Chem. 2011 Sep 9;286(36):31361-72
references: 21708945
references: J Biol Chem. 2000 Jul 21;275(29):22387-94
references: 10777514
references: Mol Cell Biochem. 2007 Jan;294(1-2):11-8
references: 17136444
references: J Biol Chem. 1993 Jan 5;268(1):74-9
references: 8380172
references: Biochemistry. 1999 Nov 9;38(45):14966-72
references: 10555978
references: J Cell Biol. 2007 Sep 24;178(7):1161-75
references: 17893242
references: J Biol Chem. 2009 Oct 30;284(44):30360-71
references: 19737925
references: Curr Genet. 1998 Oct;34(4):297-302
references: 9799363
references: J Biol Chem. 2003 Dec 26;278(52):52873-80
references: 14561769
references: J Biol Chem. 2002 Nov 15;277(46):43553-6
references: 12364341
references: Trends Biochem Sci. 2005 Jul;30(7):396-404
references: 15951180
references: Chem Phys Lipids. 2005 Dec;138(1-2):38-49
references: 16226238
references: Hum Mol Genet. 2013 Feb 1;22(3):483-92
references: 23100323
references: Eur J Biochem. 1996 Nov 1;241(3):779-86
references: 8944766
references: Nat Chem Biol. 2012 Oct;8(10):862-9
references: 22941046
references: Biochemistry. 1999 Jul 13;38(28):9031-8
references: 10413476