title: The BCL-2-like protein CED-9 of C. elegans promotes FZO-1/Mfn1,2- and EAT-3/Opa1-dependent mitochondrial fusion.
abstract: The mammalian dynamin-related guanosine triphosphatases Mfn1,2 and Opa1 are required for mitochondrial fusion. However, how their activities are controlled and coordinated is largely unknown. We present data that implicate the BCL-2-like protein CED-9 in the control of mitochondrial fusion in Caenorhabditis elegans. We demonstrate that CED-9 can promote complete mitochondrial fusion of both the outer and inner mitochondrial membrane. We also show that this fusion is dependent on the C. elegans Mfn1,2 homologue FZO-1 and the C. elegans Opa1 homologue EAT-3. Furthermore, we show that CED-9 physically interacts with FZO-1 in vivo and that the ability of CED-9 to interact with FZO-1 is important for its ability to cause mitochondrial fusion. CED-9-induced mitochondrial fusion is not required for the maintenance of mitochondrial morphology during embryogenesis or in muscle cells, at least under normal conditions and in the absence of stress. Therefore, we propose that the BCL-2-like CED-9 acts through FZO-1/Mfn1,2 and EAT-3/Opa1 to promote mitochondrial fusion in response to specific cellular signals.
authors.affiliation: Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Stéphane G
authors.initials: SG
authors.lastname: Rolland
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.forename: Charles N
authors.initials: CN
authors.lastname: David
authors.forename: Barbara
authors.initials: B
authors.lastname: Conradt
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000166:cytology / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D008561:Membrane Fusion / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D051017:Apoptosis Regulatory Proteins; D029742:Caenorhabditis elegans Proteins; C087233:Ced-9 protein, C elegans; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C543815:EAT-3 protein, C elegans; C543814:FZO-1 protein, C elegans; D020558:GTP Phosphohydrolases
references.citation: Mol Biol Cell. 2003 Jun;14(6):2303-13
references.pmid: 12808031
references.citation: J Cell Sci. 2008 Oct 15;121(Pt 20):3373-82
references.pmid: 18827010
references.citation: Trends Cell Biol. 2007 Nov;17(11):563-9
references.pmid: 17959383
references.citation: Physiology (Bethesda). 2008 Apr;23:84-94
references.pmid: 18400691
references.citation: PLoS Genet. 2008 Feb 29;4(2):e1000022
references.pmid: 18454199
references.citation: Nat Rev Mol Cell Biol. 2004 Feb;5(2):133-47
references.pmid: 15040446
references.citation: Genes Dev. 1993 Oct;7(10):1885-97
references.pmid: 8104846
references.citation: Mol Cell. 1999 Nov;4(5):815-26
references.pmid: 10619028
references.citation: Science. 1999 Mar 5;283(5407):1488-93
references.pmid: 10066163
references.citation: Mol Cell. 2004 Sep 24;15(6):999-1006
references.pmid: 15383288
references.citation: Cell. 2006 Jul 14;126(1):177-89
references.pmid: 16839885
references.citation: J Biol Chem. 2005 Jul 15;280(28):26185-92
references.pmid: 15899901
references.citation: J Cell Biol. 2002 Dec 23;159(6):931-8
references.pmid: 12499352
references.citation: J Biol Chem. 2004 Jul 2;279(27):28298-303
references.pmid: 15087460
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2169-74
references.pmid: 18250306
references.citation: Mol Biol Cell. 2003 Jun;14(6):2342-56
references.pmid: 12808034
references.citation: J Cell Biol. 2003 Jan 20;160(2):189-200
references.pmid: 12527753
references.citation: Mol Cell. 2008 Aug 22;31(4):586-597
references.pmid: 18722182
references.citation: Cell. 1998 May 15;93(4):519-29
references.pmid: 9604928
references.citation: Cell Death Differ. 2008 Dec;15(12):1838-46
references.pmid: 18756280
references.citation: Cell. 2006 Oct 20;127(2):383-95
references.pmid: 17055438
references.citation: J Biochem. 2008 Apr;143(4):449-54
references.pmid: 18174190
references.citation: Methods Mol Biol. 2006;351:203-21
references.pmid: 16988436
references.citation: J Biol Chem. 2008 May 16;283(20):13501-5
references.pmid: 18372247
references.citation: J Biol Chem. 2004 Apr 30;279(18):18792-8
references.pmid: 14970223
references.citation: Cell Death Differ. 2008 Jul;15(7):1147-52
references.pmid: 18437161
references.citation: J Cell Biol. 2009 Feb 23;184(4):569-81
references.pmid: 19237599
references.citation: Nature. 1994 May 26;369(6478):318-20
references.pmid: 7910376
references.citation: J Biol Chem. 2005 May 13;280(19):18598-603
references.pmid: 15760898
references.citation: Science. 2004 Sep 17;305(5691):1747-52
references.pmid: 15297626
references.citation: Nature. 2005 Feb 17;433(7027):754-60
references.pmid: 15716954
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11649-54
references.pmid: 17606912
references.citation: Mol Cell Biol. 1990 May;10(5):2081-9
references.pmid: 1970117
references.citation: Cell. 1994 Feb 25;76(4):665-76
references.pmid: 7907274
references.citation: Cell. 2006 Jul 14;126(1):163-75
references.pmid: 16839884
references.citation: Trends Cell Biol. 2000 Sep;10(9):369-77
references.pmid: 10932094
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15927-32
references.pmid: 15509649
references.citation: Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59
references.pmid: 18097445
references.citation: Genes Dev. 2008 Jun 15;22(12):1577-90
references.pmid: 18559474
references.citation: Neurosci Res. 2006 Jun;55(2):123-33
references.pmid: 16600410
references.citation: Genetics. 1974 May;77(1):71-94
references.pmid: 4366476
references.citation: Annu Rev Genet. 2005;39:503-36
references.pmid: 16285870
references.citation: Science. 2004 Aug 6;305(5685):858-62
references.pmid: 15297672
references.citation: J Cell Biol. 1998 Oct 19;143(2):359-73
references.pmid: 9786948
references.citation: Cell. 2009 Mar 6;136(5):926-38
references.pmid: 19269369
references.citation: Gene. 2001 Jan 24;263(1-2):103-12
references.pmid: 11223248
references.citation: Nature. 2006 Oct 12;443(7112):658-62
references.pmid: 17035996
references.citation: J Cell Sci. 2003 Jul 1;116(Pt 13):2763-74
references.pmid: 12759376
references.citation: EMBO J. 2006 Jul 12;25(13):2966-77
references.pmid: 16778770
references.citation: Biochim Biophys Acta. 2009 Jan;1793(1):20-6
references.pmid: 18691613
references.citation: J Cell Biol. 2004 Apr 26;165(2):167-73
references.pmid: 15096522
references.citation: Dev Cell. 2006 Oct;11(4):561-73
references.pmid: 17011494
references.citation: Mol Cell. 2006 Mar 17;21(6):761-73
references.pmid: 16543146
references.citation: Methods Enzymol. 1996;273:331-47
references.pmid: 8791622
references.citation: Biochim Biophys Acta. 2009 Dec;1792(12):1138-44
references.pmid: 19100831
references.citation: Curr Biol. 2009 May 12;19(9):768-73
references.pmid: 19327994
references.citation: J Cell Biol. 2009 Mar 9;184(5):707-19
references.pmid: 19255249