Trends in Cell Biology
ReviewMitochondria as the central control point of apoptosis
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.
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