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‘A one two punch’ for mitochondrial cytochrome c release
Mitochondrion 2 (2003) 223–224 www.elsevier.com/locate/mito
Editorial
‘A one two punch’ for mitochondrial cytochrome c release Programmed cell death or ‘apoptosis’ is an evolutionary conserved event that permits multicellular organisms to selectively discard cells through an intrinsic cell suicide program. Apoptosis is characterized by distinct morphological changes to the cell, and is typified by DNA fragmentation, and cell shrinkage without the loss of membrane integrity (Wyllie, 1994). Importantly, apoptosis can be influenced by internal as well as external cues that promote the removal of cells that were inappropriately produced during embryogenesis (Wyllie, 1992) or cells that have become genetically unstable (Arends and Wyllie, 1991; Eastman et al., 1994; Thompson, 1995). The molecular and cellular events culminating in an apoptotic response are poorly understood, however, recent evidence suggests the involvement of a mitochondrial regulated pathway (reviewed in Green and Reed, 1998). In this regard, perturbations to mitochondria leading to the loss of mitochondrial membrane potential, DCm, either as a result of or consequence of permeability transition (PT) pore opening have been proposed to be an important event in this process. The formation of a large multi-protein complex comprised in part by the adenine nucleotide translocator, porin/voltage dependent anion channel as well as other proteins in the mitochondrial inner and outer membrane can reportedly increase permeability of mitochondria in response to pro-apoptotic signals (Crompton et al., 1999; Narita et al., 1998; Bossy-Wetzel et al., 1998; Bradham et al., 1998). The onset of PT pore is suggested to cause large amplitude swelling, and membrane depolarization, with the release of apoptogenic factors including cytochrome c (Bossy-Wetzel et al., 1998). The mode by which cytochrome c is released by mitochondria is unknown.
While a recent model proposes the integration of BH3 domain proteins such as Bax, Bad or t-Bid the question at hand is really whether changes in mitochondrial outer membrane permeabilization are requisite for dissociation and release of cytochrome c from the inner mitochondrial membrane (Bernardi et al., 1998; Bradham et al., 1998). In the report by Yuan et al. in this issue of Mitochondrion the authors demonstrate, using an in vitro preparation of isolated mitochondria, that the pro-apoptotic factor t-Bid is sufficient to permeabilize the outer mitochondrial membrane and efficiently provoke cytochrome c release. Importantly, the authors further determine that outer mitochondrial permeability changes may not be a universally conserved feature for cytochrome c release, since digitonin in the absence of salt was unable to trigger cytochrome c release. Interestingly, ceramides alone also failed to trigger cytochrome c release in the absence of digitonin. The data extend the model and provide evidence that the BH3 domain containing factors, known to mediate cytochrome c release, do so by disrupting outer mitochondrial permeability as well as the anchoring of cytochrome c to the inner mitochondrial membrane. While the study provides compelling evidence for the release of cytochrome c by mitochondria, the relationship between PT pore onset by pro-apoptotic signals and outer mitochondrial permeability changes required for cytochrome c release was not determined. Moreover, the relationship between cytochrome c release by tBid, or ceramides upon induction of apoptosis is less clear and was not addressed in the present study. The fact that these agents can reportedly provoke apoptosis in other systems raises the question of whether mitochondrial cytochrome c release is a universally conserved event in the apoptotic pathway. Further,
1567-7249/02/$20.00 q 2002 Elsevier Science B.V. and Mitochondria Research Society. All rights reserved. doi:10.1016/S1567-7249(02)00108-3
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Editorial
whether t-Bid or any of the other BH3 domain containing proteins impact on releasable versus nonreleasable pools of cytochrome c will have to be addressed since the cytochrome c pool impinged upon may explain why certain death signals readily provoke cytochrome c release in response to prodeath signals while others do not. Nevertheless, the authors demonstrate that outer mitochondrial membrane permeability changes precede inner mitochondrial defects leading to cytochrome c release. Perhaps this ‘one two punch’ is an evolutionary conserved event that preserves mitochondrial function and indiscriminate loss of cytochrome c by cells exposed to mild or moderate stress events.
References Arends, M.J., Wyllie, A.H., 1991. Apoptosis: mechanisms and roles in pathology. Int. Rev. Exp. Pathol. 32, 223 –254. Bernardi, P., Colonna, R., Costantini, P., et al., 1998. The mitochondrial permeability transition. Biofactors 8 (3 – 4), 273–281. Bossy-Wetzel, E., Newmeyer, D.D., Green, D.R., 1998. Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J. 17 (1), 37–49. Bradham, C.A., Qian, T., Streetz, K., Trautwein, C., Brenner, D.A., Lemasters, J.J., 1998. The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. Mol. Cell. Biol. 18 (11), 6353–6364.
Crompton, M., Virji, S., Doyle, V., Johnson, N., Ward, J.M., 1999. The mitochondrial permeability transition pore. Biochem. Soc. Symp. 66, 167– 179. Eastman, A., Grant, S., Lock, R., Tritton, T., Van Houten, N., Yuan, J., 1994. Cell death in cancer and development. AACR special conference in cancer research. Cancer Res. 54 (10), 2812–2818. Green, D.R., Reed, J.C., 1998. Mitochondria and apoptosis. Science 281 (5381), 1309–1312. Narita, M., Shimizu, S., Ito, T., et al., 1998. Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc. Natl. Acad. Sci. USA 95 (25), 14681–14686. Thompson, C.B., 1995. Apoptosis in the pathogenesis and treatment of disease. Science 267 (5203), 1456–1462. Wyllie, A.H., 1992. Apoptosis and the regulation of cell numbers in normal and neoplastic tissues: an overview. Cancer Metastasis Rev. 11 (2), 95–103. Wyllie, A.H., 1994. Death from inside out: an overview. Phil. Trans. R. Soc. Lond. B Biol. Sci. 345 (1313), 237–241.
Kelly M. Regula, Lorrie A. Kirshenbaum* The Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and the Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, R2H 2A6, Canada * Corresponding author. Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre Rm. 3016, 351 Tache´ Avenue, Winnipeg, Manitoba, R2H 2A6, Canada. Tel.: þ1-204235-3661; fax: þ1-204-233-6723. E-mail address: [email protected]
Editorial
‘A one two punch’ for mitochondrial cytochrome c release Programmed cell death or ‘apoptosis’ is an evolutionary conserved event that permits multicellular organisms to selectively discard cells through an intrinsic cell suicide program. Apoptosis is characterized by distinct morphological changes to the cell, and is typified by DNA fragmentation, and cell shrinkage without the loss of membrane integrity (Wyllie, 1994). Importantly, apoptosis can be influenced by internal as well as external cues that promote the removal of cells that were inappropriately produced during embryogenesis (Wyllie, 1992) or cells that have become genetically unstable (Arends and Wyllie, 1991; Eastman et al., 1994; Thompson, 1995). The molecular and cellular events culminating in an apoptotic response are poorly understood, however, recent evidence suggests the involvement of a mitochondrial regulated pathway (reviewed in Green and Reed, 1998). In this regard, perturbations to mitochondria leading to the loss of mitochondrial membrane potential, DCm, either as a result of or consequence of permeability transition (PT) pore opening have been proposed to be an important event in this process. The formation of a large multi-protein complex comprised in part by the adenine nucleotide translocator, porin/voltage dependent anion channel as well as other proteins in the mitochondrial inner and outer membrane can reportedly increase permeability of mitochondria in response to pro-apoptotic signals (Crompton et al., 1999; Narita et al., 1998; Bossy-Wetzel et al., 1998; Bradham et al., 1998). The onset of PT pore is suggested to cause large amplitude swelling, and membrane depolarization, with the release of apoptogenic factors including cytochrome c (Bossy-Wetzel et al., 1998). The mode by which cytochrome c is released by mitochondria is unknown.
While a recent model proposes the integration of BH3 domain proteins such as Bax, Bad or t-Bid the question at hand is really whether changes in mitochondrial outer membrane permeabilization are requisite for dissociation and release of cytochrome c from the inner mitochondrial membrane (Bernardi et al., 1998; Bradham et al., 1998). In the report by Yuan et al. in this issue of Mitochondrion the authors demonstrate, using an in vitro preparation of isolated mitochondria, that the pro-apoptotic factor t-Bid is sufficient to permeabilize the outer mitochondrial membrane and efficiently provoke cytochrome c release. Importantly, the authors further determine that outer mitochondrial permeability changes may not be a universally conserved feature for cytochrome c release, since digitonin in the absence of salt was unable to trigger cytochrome c release. Interestingly, ceramides alone also failed to trigger cytochrome c release in the absence of digitonin. The data extend the model and provide evidence that the BH3 domain containing factors, known to mediate cytochrome c release, do so by disrupting outer mitochondrial permeability as well as the anchoring of cytochrome c to the inner mitochondrial membrane. While the study provides compelling evidence for the release of cytochrome c by mitochondria, the relationship between PT pore onset by pro-apoptotic signals and outer mitochondrial permeability changes required for cytochrome c release was not determined. Moreover, the relationship between cytochrome c release by tBid, or ceramides upon induction of apoptosis is less clear and was not addressed in the present study. The fact that these agents can reportedly provoke apoptosis in other systems raises the question of whether mitochondrial cytochrome c release is a universally conserved event in the apoptotic pathway. Further,
1567-7249/02/$20.00 q 2002 Elsevier Science B.V. and Mitochondria Research Society. All rights reserved. doi:10.1016/S1567-7249(02)00108-3
224
Editorial
whether t-Bid or any of the other BH3 domain containing proteins impact on releasable versus nonreleasable pools of cytochrome c will have to be addressed since the cytochrome c pool impinged upon may explain why certain death signals readily provoke cytochrome c release in response to prodeath signals while others do not. Nevertheless, the authors demonstrate that outer mitochondrial membrane permeability changes precede inner mitochondrial defects leading to cytochrome c release. Perhaps this ‘one two punch’ is an evolutionary conserved event that preserves mitochondrial function and indiscriminate loss of cytochrome c by cells exposed to mild or moderate stress events.
References Arends, M.J., Wyllie, A.H., 1991. Apoptosis: mechanisms and roles in pathology. Int. Rev. Exp. Pathol. 32, 223 –254. Bernardi, P., Colonna, R., Costantini, P., et al., 1998. The mitochondrial permeability transition. Biofactors 8 (3 – 4), 273–281. Bossy-Wetzel, E., Newmeyer, D.D., Green, D.R., 1998. Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J. 17 (1), 37–49. Bradham, C.A., Qian, T., Streetz, K., Trautwein, C., Brenner, D.A., Lemasters, J.J., 1998. The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. Mol. Cell. Biol. 18 (11), 6353–6364.
Crompton, M., Virji, S., Doyle, V., Johnson, N., Ward, J.M., 1999. The mitochondrial permeability transition pore. Biochem. Soc. Symp. 66, 167– 179. Eastman, A., Grant, S., Lock, R., Tritton, T., Van Houten, N., Yuan, J., 1994. Cell death in cancer and development. AACR special conference in cancer research. Cancer Res. 54 (10), 2812–2818. Green, D.R., Reed, J.C., 1998. Mitochondria and apoptosis. Science 281 (5381), 1309–1312. Narita, M., Shimizu, S., Ito, T., et al., 1998. Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc. Natl. Acad. Sci. USA 95 (25), 14681–14686. Thompson, C.B., 1995. Apoptosis in the pathogenesis and treatment of disease. Science 267 (5203), 1456–1462. Wyllie, A.H., 1992. Apoptosis and the regulation of cell numbers in normal and neoplastic tissues: an overview. Cancer Metastasis Rev. 11 (2), 95–103. Wyllie, A.H., 1994. Death from inside out: an overview. Phil. Trans. R. Soc. Lond. B Biol. Sci. 345 (1313), 237–241.
Kelly M. Regula, Lorrie A. Kirshenbaum* The Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and the Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, R2H 2A6, Canada * Corresponding author. Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre Rm. 3016, 351 Tache´ Avenue, Winnipeg, Manitoba, R2H 2A6, Canada. Tel.: þ1-204235-3661; fax: þ1-204-233-6723. E-mail address: [email protected]