QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 17, Issue 11, 4593-4605, November 2006

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E06-05-0377v1 17/11/4593    most recent Alert me when this article is cited Alert me if a correction is posted Services 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 Alirol, E. Articles by Scorrano, L. Search for Related Content PubMed PubMed Citation Articles by Alirol, E. Articles by Scorrano, L.

The Mitochondrial Fission Protein hFis1 Requires the Endoplasmic Reticulum Gateway to Induce Apoptosis

Emilie Alirol^*,, Dominic James, Denise Huber, Andrea Marchetto, Lodovica Vergani, Jean-Claude Martinou, and Luca Scorrano^*

*Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, I-35129 Padova, Italy; Department of Cell Biology, Sciences III, University of Geneva, CH-1211 Genève 4, Switzerland; Patterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom; and Department of Neurological Science, University of Padova, 35121 Padova, Italy

Submitted May 2, 2006; Revised August 7, 2006; Accepted August 8, 2006
Monitoring Editor: Donald Newmeyer

Mitochondrial fission ensures organelle inheritance during cell division and participates in apoptosis. The fission protein hFis1 triggers caspase-dependent cell death, by causing the release of cytochrome c from mitochondria. Here we show that mitochondrial fission induced by hFis1 is genetically distinct from apoptosis. In cells lacking the multidomain proapoptotic Bcl-2 family members Bax and Bak (DKO), hFis1 caused mitochondrial fragmentation but not organelle dysfunction and apoptosis. Similarly, a mutant in the intermembrane region of hFis1-induced fission but not cell death, further dissociating mitochondrial fragmentation from apoptosis induction. Selective correction of the endoplasmic reticulum (ER) defect of DKO cells restored killing by hFis1, indicating that death by hFis1 relies on the ER gateway of apoptosis. Consistently, hFis1 did not directly activate BAX and BAK, but induced Ca²⁺-dependent mitochondrial dysfunction. Thus, hFis1 is a bifunctional protein that independently regulates mitochondrial fragmentation and ER-mediated apoptosis.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-05-0377) on August 16, 2006.

Address correspondence to: Luca Scorrano (luca.scorrano{at}unipd.it) or Jean-Claude Martinou (Jean-Claude.Martinou{at}cellbio.unige.ch)

Abbreviations used: CRC, Ca²⁺-retaining capacity of mitochondria; CsA, cyclosporine A; DKO, Bax–/–, Bak–/–, ; DRP1, dynamin-related protein 1; ER, endoplasmic reticulum; IMS, intermembrane space; mtBAX, mitochondrially targeted BAX; mtRFP, mitochondrially targeted dsRED; NAC, N-acetylcysteine; PTP, permeability transition pore; ROS, reactive oxygen species; SERCA, sarcoplasmic endoplasmic reticulum Ca²⁺ ATPase; TMRM, tetramethyl rhodamine methyl ester.

This article has been cited by other articles:

				J. Zhao, T. Liu, S.-B. Jin, N. Tomilin, J. Castro, O. Shupliakov, U. Lendahl, and M. Nister The novel conserved mitochondrial inner-membrane protein MTGM regulates mitochondrial morphology and cell proliferation J. Cell Sci., July 1, 2009; 122(13): 2252 - 2262. [Abstract] [Full Text] [PDF]

				A. Etxebarria, O. Terrones, H. Yamaguchi, A. Landajuela, O. Landeta, B. Antonsson, H.-G. Wang, and G. Basanez Endophilin B1/Bif-1 Stimulates BAX Activation Independently from Its Capacity to Produce Large Scale Membrane Morphological Rearrangements J. Biol. Chem., February 13, 2009; 284(7): 4200 - 4212. [Abstract] [Full Text] [PDF]

				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]

				D.-F. Suen, K. L. Norris, and R. J. Youle Mitochondrial dynamics and apoptosis Genes & Dev., June 15, 2008; 22(12): 1577 - 1590. [Abstract] [Full Text] [PDF]

				K. Gillick and M. Crompton Evaluating cytochrome c diffusion in the intermembrane spaces of mitochondria during cytochrome c release J. Cell Sci., March 1, 2008; 121(5): 618 - 626. [Abstract] [Full Text] [PDF]

				K. S. Dimmer, F. Navoni, A. Casarin, E. Trevisson, S. Endele, A. Winterpacht, L. Salviati, and L. Scorrano LETM1, deleted in Wolf Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability Hum. Mol. Genet., January 15, 2008; 17(2): 201 - 214. [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]

				C. Brooks, Q. Wei, L. Feng, G. Dong, Y. Tao, L. Mei, Z.-J. Xie, and Z. Dong Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins PNAS, July 10, 2007; 104(28): 11649 - 11654. [Abstract] [Full Text] [PDF]