Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes.
Mitofusin-2 (Mfn-2) is a dynamin-like protein that is involved in the rearrangement of the outer mitochondrial membrane. Research using various experimental systems has shown that Mfn-2 is a mediator of mitochondrial fusion, an evolutionarily conserved process responsible for the surveillance of mitochondrial homeostasis. Here, we find that cardiac myocyte mitochondria lacking Mfn-2 are pleiomorphic and have the propensity to become enlarged. Consistent with an underlying mild mitochondrial dysfunction, Mfn-2-deficient mice display modest cardiac hypertrophy accompanied by slight functional deterioration. The absence of Mfn-2 is associated with a marked delay in mitochondrial permeability transition downstream of Ca(2+) stimulation or due to local generation of reactive oxygen species (ROS). Consequently, Mfn-2-deficient adult cardiomyocytes are protected from a number of cell death-inducing stimuli and Mfn-2 knockout hearts display better recovery following reperfusion injury. We conclude that in cardiac myocytes, Mfn-2 controls mitochondrial morphogenesis and serves to predispose cells to mitochondrial permeability transition and to trigger cell death.
Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, W611, Boston, MA 02118, USA.
Kyriakos N
KN
Papanicolaou
Ramzi J
RJ
Khairallah
Gladys A
GA
Ngoh
Aristide
A
Chikando
Ivan
I
Luptak
Karen M
KM
O'Shea
Dushon D
DD
Riley
Jesse J
JJ
Lugus
Wilson S
WS
Colucci
W Jonathan
WJ
Lederer
William C
WC
Stanley
Kenneth
K
Walsh
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006321:Heart / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D010539:Permeability; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014463:Ultrasonography
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; C489710:Mfn2 protein, rat; D002118:Calcium
Nature. 2005 Mar 31;434(7033):652-8
15800626
J Cell Biol. 1988 Aug;107(2):481-95
3417757
Arch Biochem Biophys. 1979 Jul;195(2):468-77
112926
Genes Dev. 2008 Jun 15;22(12):1577-90
18559474
J Cell Sci. 2004 Dec 15;117(Pt 26):6535-46
15572413
J Bioenerg Biomembr. 2009 Apr;41(2):195-214
19399598
FEBS Lett. 2002 Jul 17;523(1-3):171-6
12123827
Circulation. 2010 May 11;121(18):2012-22
20421521
J Physiol Sci. 2007 Dec;57(6):327-35
17980092
Cell. 2006 Jul 14;126(1):177-89
16839885
Nature. 2008 Dec 4;456(7222):605-10
19052620
J Biol Chem. 2005 Jul 15;280(28):26185-92
15899901
Cardiovasc Res. 2006 May 1;70(2):191-9
16497286
J Mol Cell Cardiol. 2008 Aug;45(2):313-25
18539296
Methods. 2008 Dec;46(4):288-94
18929661
Cardiovasc Res. 2008 Oct 1;80(1):30-9
18710878
Physiol Rev. 2007 Jan;87(1):99-163
17237344
Cardiovasc Res. 2008 Jan 15;77(2):387-97
18006463
Basic Res Cardiol. 2009 Mar;104(2):181-8
19242640
J Biol Chem. 2007 Aug 10;282(32):23354-61
17562700
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2878-83
11854453
Trends Endocrinol Metab. 2009 Aug;20(6):287-94
19647447
J Cell Biol. 2003 Jan 20;160(2):189-200
12527753
J Biol Chem. 2002 Sep 20;277(38):34793-9
12095984
Mol Cell Biol. 2003 Aug;23(15):5409-20
12861026
Cell. 2007 Aug 10;130(3):548-62
17693261
Biochem J. 1995 Apr 1;307 ( Pt 1):93-8
7717999
Nature. 2005 Mar 31;434(7033):658-62
15800627
J Clin Invest. 1997 Jul 1;100(1):169-79
9202069
Curr Opin Cell Biol. 2006 Dec;18(6):685-9
17046225
Mol Biol Cell. 2001 Aug;12(8):2245-56
11514614
J Cell Sci. 2001 Mar;114(Pt 5):867-74
11181170
Science. 1998 Jun 12;280(5370):1763-6
9624056
Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1651-65
16987019
Free Radic Biol Med. 2008 Sep 15;45(6):855-65
18638546
J Cell Sci. 1998 May;111 ( Pt 10):1341-9
9570752
J Mol Cell Cardiol. 2009 Dec;47(6):819-27
19703463
Cell Death Differ. 2003 Aug;10(8):870-80
12867994
J Biol Chem. 2005 Apr 1;280(13):12944-55
15668244
Cardiovasc Res. 2008 Jan 15;77(2):334-43
18006487
J Bioenerg Biomembr. 2009 Apr;41(2):113-21
19357938
J Mol Cell Cardiol. 2009 Jun;46(6):821-31
19265700
Curr Opin Cell Biol. 2006 Aug;18(4):453-9
16781135
Biophys J. 2004 Sep;87(3):2022-34
15345578
Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15927-32
15509649
Physiol Rev. 2006 Jan;86(1):369-408
16371601
J Exp Med. 2000 Oct 2;192(7):1001-14
11015441
Nat Rev Mol Cell Biol. 2007 Nov;8(11):870-9
17928812
Mol Biol Cell. 2009 Feb;20(3):1058-67
19037102
Nat Genet. 2000 Oct;26(2):207-10
11017079
Science. 2004 Aug 6;305(5685):858-62
15297672
Circ Res. 2001 Aug 31;89(5):453-60
11532907
Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1667-74
18296569
J Biol Chem. 1992 May 5;267(13):8834-9
1374381
Annu Rev Physiol. 2010;72:61-80
20148667
J Pharmacol Exp Ther. 2010 Oct;335(1):155-62
20624993
Microsc Res Tech. 1994 Mar 1;27(4):269-77
8186445
Hum Mol Genet. 2005 Jun 1;14(11):1405-15
15829499
Eur J Biochem. 1998 Dec 1;258(2):729-35
9874241
Microsc Res Tech. 1994 Feb 15;27(3):198-219
8204911
J Mol Cell Cardiol. 2010 Aug;49(2):196-209
20399788
J Clin Invest. 2007 May;117(5):1432-9
17431505
Arch Biochem Biophys. 2007 Nov 15;467(2):234-8
17904092
Biochem J. 1987 May 15;244(1):159-64
3663110
Nat Rev Mol Cell Biol. 2008 Jul;9(7):543-56
18496517
Nat Cell Biol. 2007 May;9(5):550-5
17417626
Mol Biol Cell. 2002 Dec;13(12):4343-54
12475957
Antioxid Redox Signal. 2008 Mar;10(3):621-33
18092941
Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):946-52
18407825
Nature. 2004 Jan 29;427(6973):461-5
14749836
Cell Tissue Res. 1984;238(3):577-82
6525619
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):686-91
16712778
J Biochem. 2003 Sep;134(3):333-44
14561718
Am J Physiol Cell Physiol. 2005 Mar;288(3):C757-67
15496480
Nature. 2006 Oct 12;443(7112):658-62
17035996
J Cell Sci. 2003 Jul 1;116(Pt 13):2763-74
12759376
J Biol Chem. 2003 May 9;278(19):17190-7
12598526
Nat Rev Mol Cell Biol. 2010 Sep;11(9):621-32
20683470
Traffic. 2001 Apr;2(4):235-44
11285133
Nat Genet. 2004 May;36(5):449-51
15064763
J Clin Invest. 2010 Oct;120(10):3680-7
20890047
J Biol Chem. 2003 Nov 7;278(45):44735-44
12930841
J Neurochem. 2000 May;74(5):1999-2009
10800943
Cell. 2008 Jul 25;134(2):279-90
18662543
EMBO J. 2008 Jan 9;27(1):27-37
18079695
Cell. 2010 Apr 16;141(2):280-9
20403324