Trends in Cell Biology
Volume 10, Issue 9, 1 September 2000, Pages 369-377
Journal home page for Trends in Cell Biology

Review
Mitochondria as the central control point of apoptosis

https://doi.org/10.1016/S0962-8924(00)01803-1Get rights and content

Abstract

Mitochondria play a major role in apoptosis triggered by many stimuli. They integrate death signals through Bcl-2 family members and coordinate caspase activation through the release of cytochrome c as a result of the outer mitochondrial membrane becoming permeable. The mechanisms that lead to this permeability are not yet completely understood. Here, we attempt to summarize our current view of the mechanisms that lead to the efflux of many proteins from mitochondria during apoptosis and the role played by Bcl-2 family proteins in the control of this event.

Section snippets

Morphological changes and cellular redistribution of mitochondria

According to standard morphological descriptions, mitochondria were long thought to remain unchanged during apoptosis9 but to swell during necrosis (Box 1). However, a review of the past literature on cell death, before apoptosis had even been described, reveals abnormal mitochondria in types of cell death that, retrospectively, can be classified as apoptosis. The most frequent abnormalities are a reduction in mitochondria size and a hyperdensity of their matrix, features often referred to as

Mitochondria as a major target for Bcl-2 family proteins

Currently, 15 Bcl-2 family proteins have been identified in mammals17. All contain at least one of the four conserved regions called Bcl-2 homology domains (BH1–BH4). These motifs are formed by α helices and enable the different members of the family to form either homo- or heterodimers and to regulate each other18, 19. The Bcl-2-related proteins display either antiapoptotic or proapoptotic function. The members that inhibit apoptosis, such as Bcl-2 and Bcl-xL, harbour at least three BH

The theory of the outer-mitochondrial-membrane rupture

According to the first theory, water and solutes enter the matrix during apoptosis, causing swelling of the mitochondria (Fig. 4a,b). Because the inner membrane, with its numerous cristae, has a considerably larger surface area than the outer membrane, expansion of the inner membrane upon matrix swelling can break the outer membrane, and such rupture has been observed in different apoptotic systems23. This would be expected to trigger the release and irreversible dilution in the cytosol of the

The hypothesis of cytochrome-c-conducting channels

According to the second theory, channels are formed that are large enough for the passage of soluble proteins (Fig. 4c–e). One clue to how Bcl-2 family proteins exert their mitochondrial activity has come from the three-dimensional structure of Bcl-xL (Ref. 58). Bcl-xL consists of two central, predominantly hydrophobic, α helices (α5 and α6) surrounded by five amphipathic helices58. A similar structure can be predicted for other Bcl-2 family members such as Bcl-2 and Bax, which have a high

Regulation of mitochondrial homeostasis by antiapoptotic Bcl-2 family proteins

Mitochondria play a vital role in the cell, providing most of the cell’s energy and participating in the Ca2+, redox and pH homeostasis. This means that a major mitochondrial dysfunction is likely to cause cell death. For instance, disruption of electron transport might be responsible for the increased production of reactive oxygen species (ROS) and the cytoplasmic acidification that are observed early during apoptosis. In such circumstances, the electrons that escape in large amounts from the

Concluding remarks

Progress over the past few years has led to the recognition that, in addition to their established role in generating energy for the cell, mitochondria play a key role into controlling life and death by releasing cytochrome c into the cytosol, thereby activating caspases. With a few exceptions (e.g. Fas or TNF-triggered apoptosis in certain cells), mitochondria represent an essential component of many apoptotic pathways. The physiological importance of cytochrome-c release and the subsequent

Acknowledgements

We thank Bruno Antonsson, Peter Clarke and Kinsey Maundrell for critical reading of the manuscript, Astrid Osen for the immuno-fluorescence experiment, and Christopher Hebert for artwork. Owing to space limitations, many studies could not be cited and we apologize to those researchers for their omission.

References (70)

  • J.G. Pastorino

    Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore

    J. Biol. Chem.

    (1999)
  • H. Puthalakath

    The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex

    Mol. Cell

    (1999)
  • G. Pan

    Caspase 9, Bcl-XL, and Apaf-1 form a ternary complex

    J. Biol. Chem.

    (1998)
  • G. Kroemer

    Mitochondrial control of apoptosis

    Immunol. Today

    (1997)
  • V. Petronilli

    Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence

    Biophys. J.

    (1999)
  • H. Yoshida

    Apaf1 is required for mitochondrial pathways of apoptosis and brain development

    Cell

    (1998)
  • J.J. Chou

    Solution structure of Bid, an intracellular amplifier of apoptotic signalling

    Cell

    (1999)
  • J.M. McDonnell

    Solution structure of the proapoptotic molecule Bid: a structural basis for apoptotic agonists and antagonists

    Cell

    (1999)
  • S.L. Schendel

    Ion channel activity of the BH3 only Bcl-2 family member, BID

    J. Biol. Chem.

    (1999)
  • L. Zhu

    Modulation of mitochondrial Ca2+ homeostasis by Bcl-2

    J. Biol. Chem.

    (1999)
  • I. Budihardjo

    Biochemical pathways of caspase activation during apoptosis

    Annu. Rev. Cell Dev. Biol.

    (1999)
  • S.A. Susin

    Molecular characterization of mitochondrial apoptosis-inducing factor

    Nature

    (1999)
  • S.J. Neame

    Blocking cytochrome c activity within intact neurons inhibits apoptosis

    J. Cell Biol.

    (1998)
  • P. Juin

    c-myc-induced sensitization to apoptosis is mediated through cytochrome c release

    Genes Dev.

    (1999)
  • J.F.R. Kerr

    Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics

    Br. J. Cancer

    (1972)
  • C. Rouiller

    Contribution de la microscopie électronique a l’étude du foie normal et pathologique

    Ann. Anat. Pathol.

    (1957)
  • C.R. Hackenbrock

    Chemical and physical fixation of isolated mitochondria in low-energy and high-energy states

    Proc. Natl. Acad. Sci. U. S. A.

    (1968)
  • M. Mancini

    Mitochondrial proliferation and paradoxical membrane depolarization during terminal differentiation and apoptosis in a human colon carcinoma cell line

    J. Cell Biol.

    (1997)
  • J. Zhuang

    Apoptosis, in human monocytic THP.1 cells, results in the release of cytochrome c from mitochondria prior to their ultracondensation, formation of outer membrane discontinuities and reduction in inner membrane potential

    Cell Death Differ.

    (1998)
  • I. Martinou

    The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible event

    J. Cell Biol.

    (1999)
  • A. Gross

    BCL-2 family members and the mitochondria in apoptosis

    Genes Dev.

    (1999)
  • Z.N. Oltvai

    Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death

    Cell

    (1993)
  • I.S. Goping

    Regulated targeting of BAX to mitochondria

    J. Cell Biol.

    (1998)
  • R.M. Kluck

    The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis

    Science

    (1997)
  • J. Yang

    Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked

    Science

    (1997)
  • Cited by (1743)

    View all citing articles on Scopus
    View full text