Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspectives
  • Published:

Mitochondrial fission in apoptosis

Nature Reviews Molecular Cell Biology volume 6, pages 657–663 (2005)Cite this article

Abstract

Mitochondria fuse and divide continuously within cells to form a dynamic network. One of the steps in apoptosis is the fragmentation of mitochondria, and recent evidence indicates that the mitochondrial fission machinery actively participates in the process of programmed cell death.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Dynamics of the mitochondrial network in mammalian cells.
Figure 2: Models of DRP1 mitochondrial scission.
Figure 3: Mitochondrial fragmentation.

Similar content being viewed by others

References

  1. Osteryoung, K. W. & Nunnari, J. The division of endosymbiotic organelles. Science 302, 1698–1704 (2003).

    Article  CAS  Google Scholar 

  2. Alexander, C. et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nature Genet. 26, 211–215 (2000).

    Article  CAS  Google Scholar 

  3. Delettre, C. et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nature Genet. 26, 207–210 (2000).

    Article  CAS  Google Scholar 

  4. Griparic, L., van der Wel, N. N., Orozco, I. J., Peters, P. J. & van der Bliek, A. M. Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J. Biol. Chem. 279, 18792–18798 (2004).

    Article  CAS  Google Scholar 

  5. Olichon, A. et al. Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J. Biol. Chem. 278, 7743–7746 (2003).

    Article  CAS  Google Scholar 

  6. Cipolat, S., Martins de Brito, O., Dal Zilio, B. & Scorrano, L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc. Natl Acad. Sci. USA 101, 15927–15932 (2004).

    Article  CAS  Google Scholar 

  7. Delettre, C. et al. Mutation spectrum and splicing variants in the OPA1 gene. Hum. Genet. 109, 584–591 (2001).

    Article  CAS  Google Scholar 

  8. Chen, H. et al. Mitofusins MFN1 and MFN2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell Biol. 160, 189–200 (2003).

    Article  CAS  Google Scholar 

  9. Rojo, M., Legros, F., Chateau, D. & Lombes, A. Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologues of the transmembrane GTPase Fzo. J. Cell Sci. 115, 1663–1674 (2002).

    CAS  PubMed  Google Scholar 

  10. Karbowski, M. et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and MFN2 during apoptosis. J. Cell Biol. 159, 931–938 (2002).

    Article  CAS  Google Scholar 

  11. Koshiba, T. et al. Structural basis of mitochondrial tethering by mitofusin complexes. Science 305, 858–862 (2004).

    Article  CAS  Google Scholar 

  12. Ishihara, N., Eura, Y. & Mihara, K. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J. Cell Sci. 117, 6535–6546 (2004).

    Article  CAS  Google Scholar 

  13. Meeusen, S., McCaffery, J. M. & Nunnari, J. Mitochondrial fusion intermediates revealed in vitro. Science 305, 1747–1752 (2004).

    Article  CAS  Google Scholar 

  14. Dohm, J. A., Lee, S. J., Hardwick, J. M., Hill, R. B. & Gittis, A. G. Cytosolic domain of the human mitochondrial fission protein fis1 adopts a TPR fold. Proteins 54, 153–156 (2004).

    Article  CAS  Google Scholar 

  15. Suzuki, M., Jeong, S. Y., Karbowski, M., Youle, R. J. & Tjandra, N. The solution structure of human mitochondria fission protein Fis1 reveals a novel TPR-like helix bundle. J. Mol. Biol. 334, 445–458 (2003).

    Article  CAS  Google Scholar 

  16. Praefcke, G. J. & McMahon, H. T. The dynamin superfamily: universal membrane tubulation and fission molecules? Nature Rev. Mol. Cell Biol. 5, 133–147 (2004).

    Article  CAS  Google Scholar 

  17. van der Bliek, A. M. A mitochondrial division apparatus takes shape. J. Cell Biol. 151, F1–F4 (2000).

    Article  CAS  Google Scholar 

  18. Danino, D., Moon, K. H. & Hinshaw, J. E. Rapid constriction of lipid bilayers by the mechanochemical enzyme dynamin. J. Struct. Biol. 147, 259–267 (2004).

    Article  CAS  Google Scholar 

  19. Yoon, Y., Pitts, K. R. & McNiven, M. A. Mammalian dynamin-like protein DLP1 tubulates membranes. Mol. Biol. Cell 12, 2894–2905 (2001).

    Article  CAS  Google Scholar 

  20. Karbowski, M., Jeong, S. Y. & Youle, R. J. Endophilin B1 is required for the maintenance of mitochondrial morphology. J. Cell Biol. 166, 1027–1039 (2004).

    Article  CAS  Google Scholar 

  21. Ringstad, N. et al. Endophilin/SH3p4 is required for the transition from early to late stages in clathrin-mediated synaptic vesicle endocytosis. Neuron 24, 143–154 (1999).

    Article  CAS  Google Scholar 

  22. Farsad, K. et al. Generation of high curvature membranes mediated by direct endophilin bilayer interactions. J. Cell Biol. 155, 193–200 (2001).

    Article  CAS  Google Scholar 

  23. Takei, K., McPherson, P. S., Schmid, S. L. & De Camilli, P. Tubular membrane invaginations coated by dynamin rings are induced by GTP-γ S in nerve terminals. Nature 374, 186–190 (1995).

    Article  CAS  Google Scholar 

  24. Smirnova, E., Griparic, L., Shurland, D. -L. & van der Bliek, A. M. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol. Biol. Cell 12, 2245–2256 (2001).

    Article  CAS  Google Scholar 

  25. Lee, Y. J., Jeong, S. Y., Karbowski, M., Smith, C. L. & Youle, R. J. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol. Biol. Cell 15, 5001–5011 (2004).

    Article  CAS  Google Scholar 

  26. Peters, C., Baars, T. L., Buhler, S. & Mayer, A. Mutual control of membrane fission and fusion proteins. Cell 119, 667–678 (2004).

    Article  CAS  Google Scholar 

  27. Koch, A., Schneider, G., Luers, G. H. & Schrader, M. Peroxisome elongation and constriction but not fission can occur independently of dynamin-like protein 1. J. Cell Sci. 117, 3995–4006 (2004).

    Article  CAS  Google Scholar 

  28. Nishida, K. et al. Dynamic recruitment of dynamin for final mitochondrial severance in a primitive red alga. Proc. Natl Acad. Sci. USA 100, 2146–2151 (2003).

    Article  CAS  Google Scholar 

  29. Legesse-Miller, A., Massol, R. H. & Kirchhausen, T. Constriction and Dnm1p recruitment are distinct processes in mitochondrial fission. Mol. Biol. Cell 14, 1953–1963 (2003).

    Article  CAS  Google Scholar 

  30. Mancini, M. et al. Mitochondrial proliferation and paradoxical membrane depolarization during terminal differentiation and apoptosis in a human colon carcinoma cell line. J. Cell Biol. 138, 449–469 (1997).

    Article  CAS  Google Scholar 

  31. Desagher, S. & Martinou, J. C. Mitochondria as the central control point of apoptosis. Trends Cell Biol. 10, 369–377 (2000).

    Article  CAS  Google Scholar 

  32. Frank, S. et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 1, 515–525 (2001).

    Article  CAS  Google Scholar 

  33. Pinton, P. et al. The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J. 20, 2690–2701 (2001).

    Article  CAS  Google Scholar 

  34. Jagasia, R., Grote, P., Westermann, B. & Conradt, B. DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans. Nature 433, 754–760 (2005).

    Article  CAS  Google Scholar 

  35. Capano, M. & Crompton, M. Biphasic translocation of Bax to mitochondria. Biochem. J. 367, 169–178 (2002).

    Article  CAS  Google Scholar 

  36. Karbowski, M. et al. Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J. Cell Biol. 164, 493–499 (2004).

    Article  CAS  Google Scholar 

  37. Breckenridge, D. G., Stojanovic, M., Marcellus, R. C. & Shore, G. C. Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J. Cell Biol. 160, 1115–1127 (2003).

    Article  CAS  Google Scholar 

  38. Sugioka, R., Shimizu, S. & Tsujimoto, Y. Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis. J. Biol. Chem. 279, 52726–52734 (2004).

    Article  CAS  Google Scholar 

  39. James, D. I., Parone, P. A., Mattenberger, Y. & Martinou, J. C. hFis1, a novel component of the mammalian mitochondrial fission machinery. J. Biol. Chem. 278, 36373–36379 (2003).

    Article  CAS  Google Scholar 

  40. Fannjiang, Y. et al. Mitochondrial fission proteins regulate programmed cell death in yeast. Genes Dev. 18, 2785–2797 (2004).

    Article  CAS  Google Scholar 

  41. Schinzel, A. et al. Conformational control of Bax localization and apoptotic activity by Pro168. J. Cell Biol. 164, 1021–1032 (2004).

    Article  CAS  Google Scholar 

  42. Nechushtan, A., Smith, C. L., Lamensdorf, I., Yoon, S.-H. & Youle, R. J. Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J. Cell Biol. 153, 1265–1276 (2001).

    Article  CAS  Google Scholar 

  43. Valentijn, A. J., Metcalfe, A. D., Kott, J., Streuli, C. H. & Gilmore, A. P. Spatial and temporal changes in Bax subcellular localization during anoikis. J. Cell Biol. 162, 599–612 (2003).

    Article  CAS  Google Scholar 

  44. Germain, M., Mathai, J. P., McBride, H. M. & Shore, G. C. Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis. EMBO J. 24, 1546–1556 (2005).

    Article  CAS  Google Scholar 

  45. Cuddeback, S. M. et al. Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax. J. Biol. Chem. 276, 20559–20565 (2001).

    Article  CAS  Google Scholar 

  46. Pierrat, B. et al. SH3GLB, a new endophilin-related protein family featuring an SH3 domain. Genomics 71, 222–234 (2001).

    Article  CAS  Google Scholar 

  47. Basanez, G. et al. Bax-type apoptotic proteins porate pure lipid bilayers through a mechanism sensitive to intrinsic monolayer curvature. J. Biol. Chem. 277, 49360–49365 (2002).

    Article  CAS  Google Scholar 

  48. Scorrano, L. et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev. Cell 2, 55–67 (2002).

    Article  CAS  Google Scholar 

  49. Olichon, A. et al. The human dynamin-related protein OPA1 is anchored to the mitochondrial inner membrane facing the inter-membrane space. FEBS Lett. 523, 171–176 (2002).

    Article  CAS  Google Scholar 

  50. Sesaki, H., Southard, S. M., Yaffe, M. P. & Jensen, R. E. Mgm1p, a dynamin-related GTPase, is essential for fusion of the mitochondrial outer membrane. Mol. Biol. Cell 14, 2342–2356 (2003).

    Article  CAS  Google Scholar 

  51. Kuwana, T. et al. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111, 331–342 (2002).

    Article  CAS  Google Scholar 

  52. Dorstyn, L., Mills, K., Lazebnik, Y. & Kumar, S. The two cytochrome c species, DC3 and DC4, are not required for caspase activation and apoptosis in Drosophila cells. J. Cell Biol. 167, 405–410 (2004).

    Article  CAS  Google Scholar 

  53. Dimmer, K. S. et al. Genetic basis of mitochondrial function and morphology in Saccharomyces cerevisiae. Mol. Biol. Cell 13, 847–853 (2002).

    Article  CAS  Google Scholar 

  54. Bleazard, W. et al. The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nature Cell Biol. 1, 298–304 (1999).

    Article  CAS  Google Scholar 

  55. Labrousse, A. M., Zappaterra, M. D., Rube, D. A. & van der Bliek, A. M. C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol. Cell 4, 815–826 (1999).

    Article  CAS  Google Scholar 

  56. Hales, K. G. & Fuller, M. T. Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase. Cell 90, 121–129 (1997).

    Article  CAS  Google Scholar 

  57. Shepard, K. A. & Yaffe, M. P. The yeast dynamin-like protein, Mgm1p, functions on the mitochondrial outer membrane to mediate mitochondrial inheritance. J. Cell Biol. 144, 711–720 (1999).

    Article  CAS  Google Scholar 

  58. Wong, E. D. et al. The dynamin-related GTPase, Mgm1p, is an intermembrane space protein required for maintenance of fusion competent mitochondria. J. Cell Biol. 151, 341–352 (2000).

    Article  CAS  Google Scholar 

  59. Hermann, G. J. et al. Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p. J. Cell Biol. 143, 359–373 (1998).

    Article  CAS  Google Scholar 

  60. Santel, A. & Fuller, M. Control of mitochondrial morphology by a human mitofusin. J. Cell Sci. 114, 867–874 (2001).

    CAS  PubMed  Google Scholar 

  61. Mozdy, A. D., McCaffery, J. M. & Shaw, J. M. Dnm1p GTPase-mediated mitochondrial fission is a multi-step process requiring the novel integral membrane component Fis1p. J. Cell Biol. 151, 367–380 (2000).

    Article  CAS  Google Scholar 

  62. Yoon, Y., Krueger, E. W., Oswald, B. J. & McNiven, M. A. The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol. Cell. Biol. 23, 5409–5420 (2003).

    Article  CAS  Google Scholar 

  63. Tieu, Q., Okreglak, V., Naylor, K. & Nunnari, J. The WD repeat protein, Mdv1p, functions as a molecular adaptor by interacting with Dnm1p and Fis1p during mitochondrial fission. J. Cell Biol. 158, 445–452 (2002).

    Article  CAS  Google Scholar 

  64. Cerveny, K. L., McCaffery, J. M. & Jensen, R. E. Division of mitochondria requires a novel DNM1-interacting protein, Net2p. Mol. Biol. Cell 12, 309–321 (2001).

    Article  CAS  Google Scholar 

  65. Messerschmitt, M. et al. The inner membrane protein Mdm33 controls mitochondrial morphology in yeast. J. Cell Biol. 160, 553–564 (2003).

    Article  CAS  Google Scholar 

  66. Sesaki, H. & Jensen, R. E. UGO1 encodes an outer membrane protein required for mitochondrial fusion. J. Cell Biol. 152, 1123–1134 (2001).

    Article  CAS  Google Scholar 

  67. Nemoto, Y. & De Camilli, P. Recruitment of an alternatively spliced form of synaptojanin 2 to mitochondria by the interaction with the PDZ domain of a mitochondrial outer membrane protein. EMBO J. 18, 2991–3006 (1999).

    Article  CAS  Google Scholar 

  68. Frederick, R. L., McCaffery, J. M., Cunningham, K. W., Okamoto, K. & Shaw, J. M. Yeast Miro GTPase, Gem1p, regulates mitochondrial morphology via a novel pathway. J. Cell Biol. 167, 87–98 (2004).

    Article  CAS  Google Scholar 

  69. Fransson, A., Ruusala, A. & Aspenstrom, P. Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J. Biol. Chem. 278, 6495–6502 (2003).

    Article  CAS  Google Scholar 

  70. Alto, N. M., Soderling, J. & Scott, J. D. Rab32 is an A-kinase anchoring protein and participates in mitochondrial dynamics. J. Cell Biol. 158, 659–668 (2002).

    Article  CAS  Google Scholar 

  71. Mukamel, Z. & Kimchi, A. Death-associated protein 3 localizes to the mitochondria and is involved in the process of mitochondrial fragmentation during cell death. J. Biol. Chem. 279, 36732–36738 (2004).

    Article  CAS  Google Scholar 

  72. Harder, Z., Zunino, R. & McBride, H. Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr. Biol. 14, 340–345 (2004).

    Article  CAS  Google Scholar 

  73. Tondera, D. et al. Knockdown of MTP18, a novel phosphatidylinositol 3-kinase-dependent protein, affects mitochondrial morphology and induces apoptosis. J. Biol. Chem. 279, 31544–31555 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Fell, C. Blackstone and C. Smith for valuable discussions. We regret that we could not cite all the relevant literature owing to space constraints.

Author information

Authors and Affiliations

  1. the Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Richard J. Youle & Mariusz Karbowski

Authors
  1. Richard J. Youle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariusz Karbowski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard J. Youle.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

DATABASES

Swiss-Prot

BAK

BCL2

BID

BIK

DRP1

endophilin B1

MFN1

MFN2

OPA1

Vps1

FURTHER INFORMATION

Richard Youle's laboratory

Rights and permissions

Reprints and permissions

About this article

Cite this article

Youle, R., Karbowski, M. Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol 6, 657–663 (2005). https://doi.org/10.1038/nrm1697

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1697

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing