QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 20 May 2003
doi: 10.1242/jcs.00479

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.00479v1 116/13/2763    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Santel, A. Articles by Fuller, M. T. Search for Related Content PubMed PubMed Citation Articles by Santel, A. Articles by Fuller, M. T.

Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells

Ansgar Santel^*,1, Stephan Frank^2,4, Brigitte Gaume², Michael Herrler³, Richard J. Youle² and Margaret T. Fuller^1,

¹ Departments of Developmental Biology and Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
² Biochemistry Section, Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, MD 20892, USA
³ BD Biosciences CLONTECH, Palo Alto, CA 94303, USA
⁴ Department of Neuropathology, University of Bonn, 53105 Bonn, Germany

Author for correspondence (e-mail: fuller{at}cmgm.stanford.edu

Accepted 14 March 2003

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 (Mfn1^K88T) 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 Mfn1^T109A resulted in fragmentation of mitochondria. We propose that Mfn1^T109A 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.

Key words: Mitochondria, Fusion, Fission, Fzo, GTPase, Organelle, Human, mtDNA

This article has been cited by other articles:

				K.-S. Park, A. Wiederkehr, C. Kirkpatrick, Y. Mattenberger, J.-C. Martinou, P. Marchetti, N. Demaurex, and C. B. Wollheim Selective Actions of Mitochondrial Fission/Fusion Genes on Metabolism-Secretion Coupling in Insulin-releasing Cells J. Biol. Chem., November 28, 2008; 283(48): 33347 - 33356. [Abstract] [Full Text] [PDF]

				S. Arnold, G. W. de Araujo, and C. Beyer Gender-specific regulation of mitochondrial fusion and fission gene transcription and viability of cortical astrocytes by steroid hormones J. Mol. Endocrinol., November 1, 2008; 41(5): 289 - 300. [Abstract] [Full Text] [PDF]

				S. Gandre-Babbe and A. M. van der Bliek The Novel Tail-anchored Membrane Protein Mff Controls Mitochondrial and Peroxisomal Fission in Mammalian Cells Mol. Biol. Cell, June 1, 2008; 19(6): 2402 - 2412. [Abstract] [Full Text] [PDF]

				N. Nakamura and S. Hirose Regulation of Mitochondrial Morphology by USP30, a Deubiquitinating Enzyme Present in the Mitochondrial Outer Membrane Mol. Biol. Cell, May 1, 2008; 19(5): 1903 - 1911. [Abstract] [Full Text] [PDF]

				S. L. Archer, M. Gomberg-Maitland, M. L. Maitland, S. Rich, J. G. N. Garcia, and E. K. Weir Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1{alpha}-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H570 - H578. [Abstract] [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. Drp1 Mediates Caspase-Independent Type III Cell Death in Normal and Leukemic Cells Mol. Cell. Biol., October 15, 2007; 27(20): 7073 - 7088. [Abstract] [Full Text] [PDF]

				Y. Kim, P. Zhou, L. Qian, J.-Z. Chuang, J. Lee, C. Li, C. Iadecola, C. Nathan, and A. Ding 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 J. Biol. Chem., August 10, 2007; 282(32): 23354 - 23361. [Abstract] [Full Text] [PDF]

				P. Hajek, A. Chomyn, and G. Attardi Identification of a Novel Mitochondrial Complex Containing Mitofusin 2 and Stomatin-like Protein 2 J. Biol. Chem., February 23, 2007; 282(8): 5670 - 5681. [Abstract] [Full Text] [PDF]

				S. A. Detmer and D. C. Chan Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations J. Cell Biol., February 12, 2007; 176(4): 405 - 414. [Abstract] [Full Text] [PDF]

				E. Alirol, D. James, D. Huber, A. Marchetto, L. Vergani, J.-C. Martinou, and L. Scorrano The Mitochondrial Fission Protein hFis1 Requires the Endoplasmic Reticulum Gateway to Induce Apoptosis Mol. Biol. Cell, November 1, 2006; 17(11): 4593 - 4605. [Abstract] [Full Text] [PDF]

				M. Durr, M. Escobar-Henriques, S. Merz, S. Geimer, T. Langer, and B. Westermann Nonredundant Roles of Mitochondria-associated F-Box Proteins Mfb1 and Mdm30 in Maintenance of Mitochondrial Morphology in Yeast Mol. Biol. Cell, September 1, 2006; 17(9): 3745 - 3755. [Abstract] [Full Text] [PDF]

				F. X. Soriano, M. Liesa, D. Bach, D. C. Chan, M. Palacin, and A. Zorzano Evidence for a Mitochondrial Regulatory Pathway Defined by Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator-1{alpha}, Estrogen-Related Receptor-{alpha}, and Mitofusin 2 Diabetes, June 1, 2006; 55(6): 1783 - 1791. [Abstract] [Full Text] [PDF]

				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] [PDF]

				A. Niemann, M. Ruegg, V. La Padula, A. Schenone, and U. Suter Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease J. Cell Biol., September 26, 2005; 170(7): 1067 - 1078. [Abstract] [Full Text] [PDF]

				S. Honda, T. Aihara, M. Hontani, K. Okubo, and S. Hirose Mutational analysis of action of mitochondrial fusion factor mitofusin-2 J. Cell Sci., 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]