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JCS ePress
online publication date 20 May 2003
doi: 10.1242/jcs.00479
Research Article
Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells
Ansgar Santel,
Stephan Frank,
Brigitte Gaume,
Michael Herrler,
Richard J. Youle,
and
Margaret T. Fuller*
* Author for correspondence (e-mail: fuller{at}cmgm.stanford.edu)
Mitochondrial fusion may regulate mitochondrial morphogenesis and underlie complementation between mitochondrial genomes in mammalian cells. The nuclear encoded mitochondrial proteins Mfn1 and Mfn2 are human homologues of the only known protein mediators of mitochondrial fusion, the Drosophila Fzo GTPase and Saccharomyces cerevisiae yFzo1p. Although the Mfn1 and Mfn2 genes were broadly expressed, the two genes showed different levels of mRNA expression in different tissues. Two Mfn1 transcripts were detected at similar levels in a variety of human tissues and were dramatically elevated in heart, while Mfn2 mRNA was abundantly expressed in heart and muscle tissue but present only at low levels in many other tissues. Human Mfn1 protein localized to mitochondria and participated in a high molecular weight, detergent extractable protein complex. Forced expression of Mfn1 in cultured cells caused formation of characteristic networks of mitochondria. Introduction of a point mutation in the conserved G1 region of the predicted GTPase domain (Mfn1K88T) dramatically decreased formation of mitochondrial networks upon Mfn1 overexpression, suggesting that network formation required completion of the Mfn1 GTPase cycle. Conversely, a protein variant carrying a point mutation in the G2 motif of the Mfn1 GTPase domain acted as a dominant negative: overexpression of Mfn1T109A resulted in fragmentation of mitochondria. We propose that Mfn1T109A interferes with fusion activity of endogenous Mfn1 protein, possibly by binding necessary cofactors, so to allow unopposed mitochondrial fission. Thus, Mfn1 appears to be a key player in mediating mitochondrial fusion and morphology in mammalian cells.
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|
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|
|
|
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|
|
|
|
|
|
|
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[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Bras, V. J. Yuste, G. Roue, S. Barbier, P. Sancho, C. Virely, M. Rubio, S. Baudet, J. E. Esquerda, H. Merle-Beral, et al.
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Mol. Cell. Biol.,
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27(20):
7073 - 7088.
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival
J. Exp. Med.,
September 3, 2007;
204(9):
2063 - 2074.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Shen, M. Zheng, C. Cao, C. Chen, J. Tang, W. Zhang, H. Cheng, K.-H. Chen, and R.-P. Xiao
Mitofusin-2 Is a Major Determinant of Oxidative Stress-mediated Heart Muscle Cell Apoptosis
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282(32):
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|
|
|
|
|
|
|
P. Hajek, A. Chomyn, and G. Attardi
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282(8):
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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February 12, 2007;
176(4):
405 - 414.
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[Full Text]
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|
|
|
|
|
|
|
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17(11):
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|
|
|
|
|
|
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17(9):
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|
|
|
|
|
|
|
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55(6):
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|
|
|
|
|
|
|
H. Chen and D. C. Chan
Emerging functions of mammalian mitochondrial fusion and fission
Hum. Mol. Genet.,
October 15, 2005;
14(suppl_2):
R283 - R289.
[Abstract]
[Full Text]
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|
|
|
|
|
|
|
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170(7):
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[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Honda, T. Aihara, M. Hontani, K. Okubo, and S. Hirose
Mutational analysis of action of mitochondrial fusion factor mitofusin-2
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July 15, 2005;
118(14):
3153 - 3161.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Tondera, F. Czauderna, K. Paulick, R. Schwarzer, J. Kaufmann, and A. Santel
The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells
J. Cell Sci.,
July 15, 2005;
118(14):
3049 - 3059.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Neuspiel, R. Zunino, S. Gangaraju, P. Rippstein, and H. McBride
Activated Mitofusin 2 Signals Mitochondrial Fusion, Interferes with Bax Activation, and Reduces Susceptibility to Radical Induced Depolarization
J. Biol. Chem.,
July 1, 2005;
280(26):
25060 - 25070.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Pich, D. Bach, P. Briones, M. Liesa, M. Camps, X. Testar, M. Palacin, and A. Zorzano
The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system
Hum. Mol. Genet.,
June 1, 2005;
14(11):
1405 - 1415.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Garnier, D. Fortin, J. Zoll, B. N'Guessan, B. Mettauer, E. Lampert, V. Veksler, and R. Ventura-Clapier
Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle
FASEB J,
January 1, 2005;
19(1):
43 - 52.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Ishihara, Y. Eura, and K. Mihara
Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity
J. Cell Sci.,
December 15, 2004;
117(26):
6535 - 6546.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Cipolat, O. M. de Brito, B. Dal Zilio, and L. Scorrano
OPA1 requires mitofusin 1 to promote mitochondrial fusion
PNAS,
November 9, 2004;
101(45):
15927 - 15932.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. S. Brookes, Y. Yoon, J. L. Robotham, M. W. Anders, and S.-S. Sheu
Calcium, ATP, and ROS: a mitochondrial love-hate triangle
Am J Physiol Cell Physiol,
October 1, 2004;
287(4):
C817 - C833.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Koshiba, S. A. Detmer, J. T. Kaiser, H. Chen, J. M. McCaffery, and D. C. Chan
Structural Basis of Mitochondrial Tethering by Mitofusin Complexes
Science,
August 6, 2004;
305(5685):
858 - 862.
[Abstract]
[Full Text]
[PDF]
|
|
|
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