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

ABSTRACT 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
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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.
    Molecular Biology of the Cell 01/2015; 26(6). DOI:10.1091/mbc.E14-08-1315 · 4.47 Impact Factor
    • "nd favoring its cleavage into the proapoptotic processed form ( p20Bap31 ) . This proa - poptotic protein then causes a rapid transmission of ER calcium signal to the mitochondria at close ER - mitochon - dria junctions . Finally , this calcium influx into mitochon - dria stimulates Drp1 - dependent mitochondrial fission and cytochrome c release ( Breckenridge et al . , 2003 ) ."
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    ABSTRACT: Abstract Mitochondrial dynamics is crucial for cell survival, development and homeostasis and impairment of these functions leads to neurologic disorders and metabolic diseases. The key components of mitochondrial dynamics have been identified. Mitofusins and OPA1 mediate mitochondrial fusion, whereas Drp1 is responsible for mitochondrial fission. In addition, an interplay between the proteins of the mitochondrial fission/fusion machinery and the Bcl-2 proteins, essential mediators in apoptosis, has been also described. Here, we review the molecular mechanisms regarding mitochondrial dynamics together with their role in apoptosis.
    Biological Chemistry 11/2013; 395(3). DOI:10.1515/hsz-2013-0234 · 3.27 Impact Factor
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    • "Mitochondrial hyper-fission is a conserved hallmark of the stress response in higher eukaryotes [32] [33] [34] as well as yeast [35] [36] [37] (see [38] for review). In many examples, mitochondrial fission is an early event in the PCD pathway [39] [40]. Thus, the resistance to ROS-induced programmed cell death (PCD) exhibited by cyclin C null cells [6] [7] is likely due to a defect in the extensive mitochondrial fragmentation associated with cellular damage. "
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    ABSTRACT: Mtl1 is a member of a cell wall sensor family that monitors cell wall integrity in budding yeast. In response to cell wall stress, Mtl1 activates the cell wall integrity (CWI) MAP kinase pathway which transmits this signal to the nucleus to effect changes in gene expression. One target of the CWI MAP kinase is cyclin C, a negative regulator of stress response genes. CWI activation results in cyclin C relocalization from the nucleus to the cytoplasm where it stimulates programmed cell death (PCD) before it is destroyed. This report demonstrates that under low oxidative stress conditions, a combination of membrane sensors, Mtl1 and either Wsc1 or Mid2, are required jointly to transmit the oxidative stress signal to initiate cyclin C destruction. However, when exposed to elevated oxidative stress, additional pathways independent of these three sensor proteins are activated to destroy cyclin C. In addition, N-glycosylation is important for Mtl1 function as mutating the receptor residue (Asn42) or an enzyme required for synthesis of N-acetylglucosamine (Gfa1) reduces sensor activity. Finally, combining gfa1-1 with the cyclin C null allele induces a severe synthetic growth defect. This surprising result reveals a previously unknown genetic interaction between cyclin C and plasma membrane integrity.
    Oxidative Medicine and Cellular Longevity 10/2013; 2013(13):320823. DOI:10.1155/2013/320823 · 3.36 Impact Factor
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