Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text PDF (Full Text) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Breckenridge, D. G. Articles by Shore, G. C. Search for Related Content PubMed PubMed Citation Articles by Breckenridge, D. G. Articles by Shore, G. C. Related Collections Related Article Social Bookmarking                      What's this?

¹ Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6
² Gemin X Biotechnologies Inc., Montreal, Quebec, Canada H2X 3P9

Address correspondence to Gordon C. Shore, 3655 Promenade Sir William Osler, McIntyre Medical Sciences Building (906), Dept. of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6. Tel.: (514) 398-7282. Fax: (514) 398-7384. E-mail: gordon.shore{at}mcgill.ca

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.

Key Words: apoptosis; caspase-8; BID; BAX; Drp1

^* Abbreviations used in this paper: crBAP31, caspase-resistant BAP31; cyt.c, cytochrome c; HA, hemagglutinin; OMM, outer mitochondrial membrane; RTA, reverse tet transactivating protein; TG, thapsigargin.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Article

Mitochondria sensitive to ER Ca²⁺ stores

Nicole LeBrasseur
J. Cell Biol. 2003 160: 981. [Full Text] [PDF]

This article has been cited by other articles:

• Fontenay, M., Gyan, E. (2008). Apoptotic pathways to death in myelodysplastic syndromes. haematol 93: 1288-1292 [Full Text]  
• Han, X.-J., Lu, Y.-F., Li, S.-A., Kaitsuka, T., Sato, Y., Tomizawa, K., Nairn, A. C., Takei, K., Matsui, H., Matsushita, M. (2008). CaM kinase I{alpha}-induced phosphorylation of Drp1 regulates mitochondrial morphology. J. Cell Biol. 182: 573-585 [Abstract] [Full Text]  
• Myhill, N., Lynes, E. M., Nanji, J. A., Blagoveshchenskaya, A. D., Fei, H., Carmine Simmen, K., Cooper, T. J., Thomas, G., Simmen, T. (2008). The Subcellular Distribution of Calnexin Is Mediated by PACS-2. Mol. Biol. Cell 19: 2777-2788 [Abstract] [Full Text]  
• Suen, D.-F., Norris, K. L., Youle, R. J. (2008). Mitochondrial dynamics and apoptosis. Genes Dev. 22: 1577-1590 [Abstract] [Full Text]  
• Wakana, Y., Takai, S., Nakajima, K.-i., Tani, K., Yamamoto, A., Watson, P., Stephens, D. J., Hauri, H.-P., Tagaya, M. (2008). Bap31 Is an Itinerant Protein That Moves between the Peripheral Endoplasmic Reticulum (ER) and a Juxtanuclear Compartment Related to ER-associated Degradation. Mol. Biol. Cell 19: 1825-1836 [Abstract] [Full Text]  
• Szabadkai, G., Duchen, M. R. (2008). Mitochondria: The Hub of Cellular Ca2+ Signaling. Physiology 23: 84-94 [Abstract] [Full Text]  
• Nieto-Miguel, T., Fonteriz, R. I., Vay, L., Gajate, C., Lopez-Hernandez, S., Mollinedo, F. (2007). Endoplasmic Reticulum Stress in the Proapoptotic Action of Edelfosine in Solid Tumor Cells. Cancer Res. 67: 10368-10378 [Abstract] [Full Text]  
• Kolar, S. S. N., Barhoumi, R., Callaway, E. S., Fan, Y.-Y., Wang, N., Lupton, J. R., Chapkin, R. S. (2007). Synergy between docosahexaenoic acid and butyrate elicits p53-independent apoptosis via mitochondrial Ca2+ accumulation in colonocytes. Am. J. Physiol. Gastrointest. Liver Physiol. 293: G935-G943 [Abstract] [Full Text]  
• Bras, M., Yuste, V. J., Roue, G., Barbier, S., Sancho, P., Virely, C., Rubio, M., Baudet, S., Esquerda, J. E., Merle-Beral, H., Sarfati, M., Susin, S. A. (2007). Drp1 Mediates Caspase-Independent Type III Cell Death in Normal and Leukemic Cells. Mol. Cell. Biol. 27: 7073-7088 [Abstract] [Full Text]  
• Kim, Y., Zhou, P., Qian, L., Chuang, J.-Z., Lee, J., Li, C., Iadecola, C., Nathan, C., Ding, A. (2007). MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J. Exp. Med. 204: 2063-2074 [Abstract] [Full Text]  
• Brooks, C., Wei, Q., Feng, L., Dong, G., Tao, Y., Mei, L., Xie, Z.-J., Dong, Z. (2007). Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Proc. Natl. Acad. Sci. USA 104: 11649-11654 [Abstract] [Full Text]  
• Wasiak, S., Zunino, R., McBride, H. M. (2007). Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J. Cell Biol. 177: 439-450 [Abstract] [Full Text]  
• Bredesen, D. E. (2007). Key Note Lecture: Toward a Mechanistic Taxonomy for Cell Death Programs. Stroke 38: 652-660 [Abstract] [Full Text]  
• Sharon-Friling, R., Goodhouse, J., Colberg-Poley, A. M., Shenk, T. (2006). Human cytomegalovirus pUL37x1 induces the release of endoplasmic reticulum calcium stores. Proc. Natl. Acad. Sci. USA 103: 19117-19122 [Abstract] [Full Text]  
• Parone, P. A., James, D. I., Da Cruz, S., Mattenberger, Y., Donze, O., Barja, F., Martinou, J.-C. (2006). Inhibiting the mitochondrial fission machinery does not prevent bax/bak-dependent apoptosis.. Mol. Cell. Biol. 26: 7397-7408 [Abstract] [Full Text]  
• Dimmer, K. S., Scorrano, L. (2006). (De)constructing Mitochondria: What For?. Physiology 21: 233-241 [Abstract] [Full Text]  
• Browman, D. T., Resek, M. E., Zajchowski, L. D., Robbins, S. M. (2006). Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins that define lipid-raft-like domains of the ER. J. Cell Sci. 119: 3149-3160 [Abstract] [Full Text]  
• YOSHINAGA, K., FUJIMOTO, M., ARIMURA, S.-I., TSUTSUMI, N., UCHIMIYA, H., KAWAI-YAMADA, M. (2006). The Mitochondrial Fission Regulator DRP3B Does Not Regulate Cell Death in Plants. ANN BOT (LOND) 97: 1145-1149 [Abstract] [Full Text]  
• Piwocka, K., Vejda, S., Cotter, T. G., O'Sullivan, G. C., McKenna, S. L. (2006). Bcr-Abl reduces endoplasmic reticulum releasable calcium levels by a Bcl-2-independent mechanism and inhibits calcium-dependent apoptotic signaling. Blood 107: 4003-4010 [Abstract] [Full Text]  
• Szczesna-Skorupa, E., Kemper, B. (2006). BAP31 Is Involved in the Retention of Cytochrome P450 2C2 in the Endoplasmic Reticulum. J. Biol. Chem. 281: 4142-4148 [Abstract] [Full Text]  
• Hidvegi, T., Schmidt, B. Z., Hale, P., Perlmutter, D. H. (2005). Accumulation of Mutant {alpha}1-Antitrypsin Z in the Endoplasmic Reticulum Activates Caspases-4 and -12, NF{kappa}B, and BAP31 but Not the Unfolded Protein Response. J. Biol. Chem. 280: 39002-39015 [Abstract] [Full Text]  
• Chess, P. R., O'Reilly, M. A., Sachs, F., Finkelstein, J. N. (2005). Reactive oxidant and p42/44 MAP kinase signaling is necessary for mechanical strain-induced proliferation in pulmonary epithelial cells. J. Appl. Physiol. 99: 1226-1232 [Abstract] [Full Text]  
• Stojanovic, M., Germain, M., Nguyen, M., Shore, G. C. (2005). BAP31 and Its Caspase Cleavage Product Regulate Cell Surface Expression of Tetraspanins and Integrin-mediated Cell Survival. J. Biol. Chem. 280: 30018-30024 [Abstract] [Full Text]  
• Ivanovska, I., Hardwick, J. M. (2005). Viruses activate a genetically conserved cell death pathway in a unicellular organism. J. Cell Biol. 170: 391-399 [Abstract] [Full Text]  
• Neuspiel, M., Zunino, R., Gangaraju, S., Rippstein, P., McBride, H. (2005). Activated Mitofusin 2 Signals Mitochondrial Fusion, Interferes with Bax Activation, and Reduces Susceptibility to Radical Induced Depolarization. J. Biol. Chem. 280: 25060-25070 [Abstract] [Full Text]  
• Liu, H., Baliga, R. (2005). Endoplasmic Reticulum Stress-Associated Caspase 12 Mediates Cisplatin-Induced LLC-PK1 Cell Apoptosis. J. Am. Soc. Nephrol. 16: 1985-1992 [Abstract] [Full Text]  
• Mathai, J. P., Germain, M., Shore, G. C. (2005). BH3-only BIK Regulates BAX,BAK-dependent Release of Ca2+ from Endoplasmic Reticulum Stores and Mitochondrial Apoptosis during Stress-induced Cell Death. J. Biol. Chem. 280: 23829-23836 [Abstract] [Full Text]  
• Maag, R. S., Mancini, M., Rosen, A., Machamer, C. E. (2005). Caspase-resistant Golgin-160 Disrupts Apoptosis Induced by Secretory Pathway Stress and Ligation of Death Receptors. Mol. Biol. Cell 16: 3019-3027 [Abstract] [Full Text]  
• Yoon, Y. (2005). Regulation of Mitochondrial Dynamics: Another Process Modulated by Ca2+ Signals?. Sci Signal 2005: pe18-pe18 [Abstract] [Full Text]  
• Oursler, M. J., Bradley, E. W., Elfering, S. L., Giulivi, C. (2005). Native, not nitrated, cytochrome c and mitochondria-derived hydrogen peroxide drive osteoclast apoptosis. Am. J. Physiol. Cell Physiol. 288: C156-C168 [Abstract] [Full Text]  
• Sugioka, R., Shimizu, S., Tsujimoto, Y. (2004). Fzo1, a Protein Involved in Mitochondrial Fusion, Inhibits Apoptosis. J. Biol. Chem. 279: 52726-52734 [Abstract] [Full Text]  
• Fannjiang, Y., Cheng, W.-C., Lee, S. J., Qi, B., Pevsner, J., McCaffery, J. M., Hill, R. B., Basanez, G., Hardwick, J. M. (2004). Mitochondrial fission proteins regulate programmed cell death in yeast. Genes Dev. 18: 2785-2797 [Abstract] [Full Text]  
• Crow, M. T., Mani, K., Nam, Y.-J., Kitsis, R. N. (2004). The Mitochondrial Death Pathway and Cardiac Myocyte Apoptosis. Circ. Res. 95: 957-970 [Abstract] [Full Text]  
• Lee, Y.-j., Jeong, S.-Y., Karbowski, M., Smith, C. L., Youle, R. J. (2004). Roles of the Mammalian Mitochondrial Fission and Fusion Mediators Fis1, Drp1, and Opa1 in Apoptosis. Mol. Biol. Cell 15: 5001-5011 [Abstract] [Full Text]  
• Brookes, P. S., Yoon, Y., Robotham, J. L., Anders, M. W., Sheu, S.-S. (2004). Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am. J. Physiol. Cell Physiol. 287: C817-C833 [Abstract] [Full Text]  
• Karbowski, M., Jeong, S.-Y., Youle, R. J. (2004). Endophilin B1 is required for the maintenance of mitochondrial morphology. J. Cell Biol. 166: 1027-1039 [Abstract] [Full Text]  
• Chandra, D., Choy, G., Deng, X., Bhatia, B., Daniel, P., Tang, D. G. (2004). Association of Active Caspase 8 with the Mitochondrial Membrane during Apoptosis: Potential Roles in Cleaving BAP31 and Caspase 3 and Mediating Mitochondrion-Endoplasmic Reticulum Cross Talk in Etoposide-Induced Cell Death. Mol. Cell. Biol. 24: 6592-6607 [Abstract] [Full Text]  
• Tondera, D., Santel, A., Schwarzer, R., Dames, S., Giese, K., Klippel, A., Kaufmann, J. (2004). Knockdown of MTP18, a Novel Phosphatidylinositol 3-Kinase-dependent Protein, Affects Mitochondrial Morphology and Induces Apoptosis. J. Biol. Chem. 279: 31544-31555 [Abstract] [Full Text]  
• Karbowski, M., Arnoult, D., Chen, H., Chan, D. C., Smith, C. L., Youle, R. J. (2004). Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J. Cell Biol. 164: 493-499 [Abstract] [Full Text]  
• Adams, J. M. (2003). Ways of dying: multiple pathways to apoptosis. Genes Dev. 17: 2481-2495 [Full Text]  
• Ruffolo, S. C., Shore, G. C. (2003). BCL-2 Selectively Interacts with the BID-induced Open Conformer of BAK, Inhibiting BAK Auto-oligomerization. J. Biol. Chem. 278: 25039-25045 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents