(21) THE PERMEABILITY TRANSITION PORE SIGNALS APOPTOSIS BY DIRECTING BAX TRANSLOCATION

F. Ichas¹, M.K. Bauer², G.T. Hanson³, A. Schubert², S. Grimm², S.J. Remington³, R.J. Youle⁴ and F. De Giorgi^1
1European Institute of Chemistry and Biology, and INSERM EMI-U.9929 Mitochondrial Physiology, Victor Segalen-Bordeaux 2 University, 33076 Bordeaux cedex, France
²Max-Planck-Institute for Biochemistry, 82152 Martinsried, Germany
³Institute of Molecular Biology and Departments of Chemistry and Physics, University of Oregon, Eugene, Oregon 97403, USA
⁴Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA

Early during apoptosis, cytochrome c is suddenly released by all the mitochondria of the cell committed to death [1]. While the mechanism of this event remains largely unknown, such release results in the activation of cytosolic caspases [2, 3] that in turn, are responsible for acquisition of the apoptotic phenotype [4]. Using recombinant biosensors and kinetic subcellular fluorescence imaging, we show here that directed repetitive gatings of the mitochondrial permeability transition pore (PTP) [5-7] in the live cell signal apoptosis by causing delayed “all-or-nothing” cytochrome c release and caspase activation. In contrast to currently held views [8, 9], we find that PTP gating in situ is not associated with mitochondrial swelling that would cause a leak of cytochrome c through mechanical defects of the outer mitochondrial membrane. Instead, we observe that PTP operation directs a coordinated redistribution of the cytosolic protein Bax [10] to the outer membrane of the organelle, where it progressively forms clusters, distinct from these formed by VDAC,  and capable of providing an efflux route for cytochrome c.

  [1]  Goldstein, J.C., et al. (2000) Nat. Cell Biol. 2:156-162
  [2]  Liu, X., et al. (1996) Cell 86:147-157
  [3]  Bossy-Wetzel, E., et al. (1998) EMBO J 17:37-49
  [4]  Green, D. and Kroemer, G. (1998) Trends Cell Biol. 8:267-271
  [5]  Ichas, F., et al. (1997) Cell 89:1145-1153
  [6]  Marzo, I. et al. (1998) Science 281:2027-2031
  [7]  Bauer, M.K., et al. (1999) J. Cell Biol. 147:1493-1502
  [8]  Martinou, J.C., et al. (2000) Nat. Cell Biol. 2:41-43
  [9]  Matsuyama, S., et al. (2000) Nat. Cell Biol. 2:318-325 
[10]  Nechushtan, A., et al. (1999) EMBO J. 18:2330-2341

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