Caspase Cleavage Product Of BAP31 Induces Mitochondrial Fission Through Endoplasmic Reticulum Calcium Signals, Enhancing Cytochrome C Release To The Cytosol.

Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6.
The Journal of Cell Biology (Impact Factor: 9.83). 04/2003; 160(7):1115-27. DOI: 10.1083/jcb.200212059
Source: PubMed


Stimulation of cell surface death receptors activates caspase-8, which targets a limited number of substrates including BAP31, an integral membrane protein of the endoplasmic reticulum (ER). Recently, we reported that a caspase-resistant BAP31 mutant inhibited several features of Fas-induced apoptosis, including the release of cytochrome c (cyt.c) from mitochondria (Nguyen, M., D.G. Breckenridge, A. Ducret, and G.C. Shore. 2000. Mol. Cell. Biol. 20:6731-6740), implicating ER-mitochondria crosstalk in this pathway. Here, we report that the p20 caspase cleavage fragment of BAP31 can direct pro-apoptotic signals between the ER and mitochondria. Adenoviral expression of p20 caused an early release of Ca2+ from the ER, concomitant uptake of Ca2+ into mitochondria, and mitochondrial recruitment of Drp1, a dynamin-related protein that mediates scission of the outer mitochondrial membrane, resulting in dramatic fragmentation and fission of the mitochondrial network. Inhibition of Drp1 or ER-mitochondrial Ca2+ signaling prevented p20-induced fission of mitochondria. p20 strongly sensitized mitochondria to caspase-8-induced cyt.c release, whereas prolonged expression of p20 on its own ultimately induced caspase activation and apoptosis through the mitochondrial apoptosome stress pathway. Therefore, caspase-8 cleavage of BAP31 at the ER stimulates Ca2+-dependent mitochondrial fission, enhancing the release of cyt.c in response to this initiator caspase.

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Available from: Richard Marcellus, Feb 23, 2015
    • "Stressinduced mitochondrial hyperfission is conserved from yeast to mammals and represents an early morphological adaptation of the stress response (Youle and van der Bliek 2012). Mitochondrial hyperfission has been associated with the release of sequestered apoptotic factors (Frank et al. 2001; Breckenridge et al. 2003) while preventing fission protects cells from PCD. For example, mutants lacking Dnm1 or Fis1 are resistant to ROS-induced PCD (Fannjiang et al. 2004). "
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    ABSTRACT: Apoptosis or programmed cell death (PCD) was initially described in metazoans as a genetically controlled process leading to intracellular breakdown and engulfment by a neighboring cell . This process was distinguished from other forms of cell death like necrosis by maintenance of plasma membrane integrity prior to engulfment and the well-defined genetic system controlling this process. Apoptosis was originally described as a mechanism to reshape tissues during development. Given this context, the assumption was made that this process would not be found in simpler eukaryotes such as budding yeast. Although basic components of the apoptotic pathway were identified in yeast, initial observations suggested that it was devoid of prosurvival and prodeath regulatory proteins identified in mammalian cells. However, as apoptosis became extensively linked to the elimination of damaged cells, key PCD regulatory proteins were identified in yeast that play similar roles in mammals. This review highlights recent discoveries that have permitted information regarding PCD regulation in yeast to now inform experiments in animals. Copyright © 2015 by the Genetics Society of America.
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    • "In all organisms examined, exposure to exogenous stress shifts the balance between mitochondrial fission and fusion dramatically toward fission (Igaki et al., 2000; Frank et al., 2001; Karbowski et al., 2002; Vieira et al., 2002; Breckenridge et al., 2003; for review, see Hoppins and Nunnari, 2012). Although the basic fission machinery is required for the extensive mitochondrial fragmentation observed after stress, the signal that triggers this response has been unknown. "
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    ABSTRACT: Mitochondria are dynamic organelles that undergo constant fission and fusion cycles. In response to cellular damage, this balance is shifted dramatically toward fission. The cyclin C-Cdk8 kinase regulates transcription of diverse gene sets. Using knockout mouse embryonic fibroblasts (MEF), we demonstrate that cyclin C directs the extensive mitochondrial scission induced by the anti-cancer drug cisplatin or oxidative stress. This activity is independent of transcriptional regulation as Cdk8 is not required for this activity. Furthermore, adding purified cyclin C to unstressed permeabilized MEF cultures induced complete mitochondrial fragmentation that is dependent on the fission factors Drp1 and Mff. To regulate fission, a portion of cyclin C translocates from the nucleus to the cytoplasm where it associates with Drp1 and is required for its enhanced mitochondrial in oxidatively stressed cells. In addition, although Hela cells regulate cyclin C in a manner similar to MEF cells, U2OS osteosarcoma cultures display constitutively cytoplasmic cyclin C and semifragmented mitochondria. Finally, cyclin C, but not Cdk8, is required for loss of mitochondrial outer membrane permeability and apoptosis in cells treated with cisplatin. In conclusion, this study suggests that cyclin C connects stress-induced mitochondrial hyper-fission and programmed cell death in mammalian cells. © 2015 by The American Society for Cell Biology.
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    • "This proapoptotic protein then causes a rapid transmission of ER calcium signal to the mitochondria at close ER-mitochondria junctions. Finally, this calcium influx into mitochondria stimulates Drp1-dependent mitochondrial fission and cytochrome c release (Breckenridge et al., 2003). Nevertheless, little is known about the mechanisms by which hFis1 could regulate apoptosis. "
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