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Regulation of Ca2+-induced permeability transition by Bcl-2 is antagonized by Drp1 and hFis1

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Abstract

The regulation of mitochondrial permeability transition (MPT) is essential for cell survival. Un-controlled opening of the MPT pore is often associated with cell death. Anti-death protein Bcl-2 can block MPT as assessed by the enhanced capacity of mitochondria to accumulate and retain Ca2+. We report here that two proteins of the mitochondrial fission machinery, dynamin-related protein (Drp1) and human mitochondrial fission protein (hFis1), have an antagonistic effect on Bcl-2. Drp1, with the assistance of hFis1, sensitizes cells to MPT by reducing the mitochondrial Ca2+ retention capacity (CRC). While the reduction of CRC by Drp1/hFis1 is linked to mitochondrial fission, the antagonism between Bcl-2 and Drp1 appears to be mediated by mutually exclusive interactions of the two proteins with hFis1. The complexity of protein–protein interactions demonstrated in the present study suggests that in addition to the previously described role of Bcl-2 in the control of apoptosis, Bcl-2 may also participate directly or indirectly in the regulation of mitochondrial fission.

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References

  1. Orrenius S, Nicotera P: Regulation of cell death: The calcium-apoptosis link. Nat Rev Mol Cell Biol 4: 552–565, 2003

    Article  CAS  PubMed  Google Scholar 

  2. Jiang S, Chow SC, Nicotera P, Orrenius S: Intracellular Ca2+ signals activate apoptosis in thymocytes: Studies using the Ca2+-ATPase inhibitor Thapsigargin. Exp Cell Res 212: 84–92,1994

    Article  CAS  PubMed  Google Scholar 

  3. McGinnis KM, Gnegy ME, Wang KKW: Alterations of extracellular calcium elicit selective modes of cell death and protease activation in SH-SY5Y human neuroblastoma cells. J Neurochem 72: 1853–1863, 1999

    Article  CAS  PubMed  Google Scholar 

  4. Kuo TH, Kim H-RC, Zhu Lp, Yu Y, Lin HM, Tsang W: Modulation of endoplasmic reticulum calcium pump Bcl-2. Oncogene 17: 1903–1910, 1998

    Article  CAS  PubMed  Google Scholar 

  5. Zhu LP, Yu XD, Ling S, Brown RA, Kuo TH: Mitochondrial Ca2+ homeostasis in the regulation of apoptotic and necrotic cell deaths. Cell Calcium 28: 107–117, 2000

    Article  CAS  PubMed  Google Scholar 

  6. Zhu LP, Yu Y, Chua BHL, Ho YS, Kuo TH: Regulation of sodium–calcium exchange and mitochondrial energetics by Bcl-2 in the heart of transgenic mice. J Mol Cell Cardio 33: 2135–2144, 2001

    Article  CAS  Google Scholar 

  7. Hansford RG: Physiological role of mitochondrial transport. J Bioenerg Biomembr 26: 495–508, 1994

    Article  CAS  PubMed  Google Scholar 

  8. Di Lisa F, Menabo R, Canton M, Barile M, Bernardi P: Opening of the mitochondriral permeability transition pore causes depletion of mitochondrial and cytosolic NAD and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J Biol Chem 276: 2571–2575, 200

  9. Crompton M: Bax, Bid and the permeabilization of the mitochondrial outer membrane in apoptosis. Curr Opin Cell Biol 12: 414–419, 2000

    Article  CAS  PubMed  Google Scholar 

  10. Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA., Mannella CA., Korsmeyer SJ: A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2: 55–67, 2002

    Article  CAS  PubMed  Google Scholar 

  11. Kuwana T, Mackey MR, Perkins G, Ellisman MR, Latterich M, Schneiter R, Green DR, Newmeyer DD: Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111: 331–342, 2002

    Article  CAS  PubMed  Google Scholar 

  12. Annis MG, Zamzami N, Zhu W, Penn LZ, Kroemer G, Leber B, Andrews DW: Endoplasmic reticulum localized Bcl-2 prevents apoptosis when redistribution of cytochrome c is a late event. Oncogene 20: 1939–1952, 2001

    Article  CAS  PubMed  Google Scholar 

  13. Green RG, Kroemer G: The pathophysiology of mitochondrial cell death. Science ([0-9]+): 626–629, 2004

    CAS  PubMed  Google Scholar 

  14. Bernardi P: Mitochondrial transport of cations: Channels, exchangers and permeability transition. Physiol Rev 79: 1127–1155, 1999

    CAS  PubMed  Google Scholar 

  15. Murphy AN, Bredesen DE, Cortopassi G, Wang E, Fiskum G: Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc Nat Acad Sci USA 93: 9893–9898, 1996

    CAS  PubMed  Google Scholar 

  16. Zhu L, Ling S, Yu XD, Venkatesh LK, Subramanian T, Chinnadurai G, Kuo TH: Modulation of mitochondrial Ca2+ homeostasis by Bcl-2. J Biol Chem 274: 33267–33273, 1999

    CAS  PubMed  Google Scholar 

  17. Bereiter-Hahn J, Voth M: Dynamics of mitochondria in living cells: Shape changes, dislocation, fusion and fission of mitochondria. Microsc Res Technol ([0-9]+): 198–219, 1994

    CAS  Google Scholar 

  18. Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM: A human dynamin-related protein controls the distribution of mitochodria. J Cell Biol ([0-9]+): 351–358, 1998

    CAS  PubMed  Google Scholar 

  19. Pitts KR, Yoon Y, Krueger EW, McNiven MA: The dynamin-like protein DLP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells. Mol Biol Cell 10: 4403–4417, 1999

    CAS  PubMed  Google Scholar 

  20. Smirnova E, Griparic L, Shurland DL, van der Bliek, AM: Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12: 2245–2256, 2001

    CAS  PubMed  Google Scholar 

  21. Bleazard W, McCaffery JM, King EJ, Bale S, Mozdy A, Tieu Q, Nunnari J Shaw JM: The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat Cell Biol 1: 298–304, 1999

    CAS  PubMed  Google Scholar 

  22. Labrousse AM, Zappaterra MD, Rube DA, van der Bliek AM: C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol Cell 4: 815–826, 1999

    CAS  PubMed  Google Scholar 

  23. Yoon Y, Krueger EW, Oswald BJ, McNiven MA: The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 15: 5409–5420, 2003

    Google Scholar 

  24. James DI, Parone PA, Mattenberger Y, Martinou JC: hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem 278: 36373–36379, 2003

    CAS  PubMed  Google Scholar 

  25. Stojanovski D, Koutsopoulos OS, Okamoto K Ryan MT: Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J. Cell Sci. ([0-9]+): 1201–1210, 2004

    CAS  PubMed  Google Scholar 

  26. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RL: The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1: 515–525, 2001

    CAS  PubMed  Google Scholar 

  27. Frieden M, James D, Castelbou C, Danckaert A, Martinou JC, Demaurex N: Ca2+ homeostasis during mitochondrial fragmentation and perinucear clustering induced by hFis1. J Biol Chem 279: 22704–22714, 2004

    CAS  PubMed  Google Scholar 

  28. Zhu W, Leber B, Andrews DW: Cytoplasmic O-glycosylation prevents cell surface transport of E-cadherin during apoptosis. EMBO J 20: 5999–6007, 2001

    CAS  PubMed  Google Scholar 

  29. Moreadith RW, Fiskum G: Isolation of mitochondria from ascites tumor cells permeabilized with digitonin. Anal Biochem 137: 360–367, 1984

    CAS  PubMed  Google Scholar 

  30. Evetodienko YV, Teplova VV, Azarashvily TS, Kudin A, Prusakova O, Virtanen I, Saris NEL: The Ca2+ threshold for the mitochondrial permeability transition and the content of proteins related to Bcl-2 in rat liver and Zajdela hepatoma mitochondria. Mol Cell Biochem 194: 251–256, 1999

    PubMed  Google Scholar 

  31. Liu BF, Xu X, Fridman R, Muallem S, Kuo TH: Consequence of functional expression of the plasma membrane Ca2+ pump isoform 1a. J Biol Chem 271: 5536–5544, 1996

    CAS  PubMed  Google Scholar 

  32. Zhu W, Cowie A, Wasfy GW, Penn LZ, Leber B, Andrews DW: Bcl-2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types. EMBO J 15: 4130–4141, 1996

    CAS  PubMed  Google Scholar 

  33. Suzuki M, Jeong SY, Karbowski M, Youle RJ, Tjandra N: The solution structure of human mitochondria fission protein Fis1 reveals a novel TPR-like helix bundle. J Mol Biol 334: 445–458, 2003

    CAS  PubMed  Google Scholar 

  34. Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A, Santel A, Fuller M. Smith CL, Youle RJ: Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 159: 931–938, 2002

    CAS  PubMed  Google Scholar 

  35. Ichas F, Jouaville LS, Mazat JP: Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89: 1145–1153, 1997

    CAS  PubMed  Google Scholar 

  36. Legros F, Lombes A, Frachon P, Rojo M; Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol Biol Cell 13: 4343–4354, 2002

    CAS  PubMed  Google Scholar 

  37. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ: Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15: 5001–5011, 2004

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Wayne State University School of Medicine, Detroit, MI, U.S.A.

    Dejuan Kong, Liping Xu, Yingjie Yu & Tuan H. Kuo

  2. Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada

    Weijia Zhu & David W. Andrews

  3. Department of Anesthesiology, and Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, U.S.A.

    Yisang Yoon

  4. Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI, 48201, U.S.A.

    Tuan H. Kuo

Authors
  1. Dejuan Kong
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  2. Liping Xu
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  3. Yingjie Yu
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  4. Weijia Zhu
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  5. David W. Andrews
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  6. Yisang Yoon
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  7. Tuan H. Kuo
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Correspondence to Tuan H. Kuo.

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Kong, D., Xu, L., Yu, Y. et al. Regulation of Ca2+-induced permeability transition by Bcl-2 is antagonized by Drp1 and hFis1. Mol Cell Biochem 272, 187–199 (2005). https://doi.org/10.1007/s11010-005-7323-3

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  • DOI: https://doi.org/10.1007/s11010-005-7323-3

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