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Bcl-x(L) blocks a mitochondrial inner membrane channel and prevents Ca2+ overload-mediated cell death

Tornero, Daniel LU ; Posadas, Inmaculada and Ceña, Valentín (2011) In PLoS One 6(6). p.20423-20423
Abstract

Apoptosis is an active process that plays a key role in many physiological and pathological conditions. One of the most important organelles involved in apoptosis regulation is the mitochondrion. An increase in intracellular Ca(2+) is a general mechanism of toxicity in neurons which occurs in response to different noxious stimuli like excitotoxicity and ischemia producing apoptotic and necrotic cell death through mitochondria-dependent mechanisms. The Bcl-2 family of proteins modulate the release of pro-apoptotic factors from the mitochondrial intermembrane space during cell death induction by different stimuli. In this work, we have studied, using single-cell imaging and patch-clamp single channel recording, the mitochondrial... (More)

Apoptosis is an active process that plays a key role in many physiological and pathological conditions. One of the most important organelles involved in apoptosis regulation is the mitochondrion. An increase in intracellular Ca(2+) is a general mechanism of toxicity in neurons which occurs in response to different noxious stimuli like excitotoxicity and ischemia producing apoptotic and necrotic cell death through mitochondria-dependent mechanisms. The Bcl-2 family of proteins modulate the release of pro-apoptotic factors from the mitochondrial intermembrane space during cell death induction by different stimuli. In this work, we have studied, using single-cell imaging and patch-clamp single channel recording, the mitochondrial mechanisms involved in the neuroprotective effect of Bcl-x(L) on Ca(2+) overload-mediated cell death in human neuroblastoma SH-SY5Y cells. We have found that Bcl-x(L) neuroprotective actions take place at mitochondria where this antiapoptotic protein delays both mitochondrial potential collapse and opening of the permeability transition pore by preventing Ca(2+)-mediated mitochondrial multiple conductance channel opening. Bcl-x(L) neuroprotective actions were antagonized by the Bcl-x(L) inhibitor ABT-737 and potentiated by the Ca(2+) chelator BAPTA-AM. As a consequence, this would prevent free radical production, mitochondrial membrane permeabilization, release from mitochondria of pro-apoptotic molecules, caspase activation and cellular death.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Apoptosis, Biological Transport, Biphenyl Compounds, Calcium, Caspases, Cell Line, Tumor, Egtazic Acid, Gene Expression Regulation, Humans, Ion Channel Gating, Ion Channels, Ionomycin, Membrane Potential, Mitochondrial, Mitochondria, Mitochondrial Membranes, Nitrophenols, Patch-Clamp Techniques, Permeability, Piperazines, Single-Cell Analysis, Sulfonamides, bcl-X Protein
in
PLoS One
volume
6
issue
6
pages
20423 - 20423
publisher
Public Library of Science
external identifiers
  • Scopus:79957936182
ISSN
1932-6203
DOI
10.1371/journal.pone.0020423
language
English
LU publication?
no
id
815cf627-0598-4750-8055-67f2c5ac89a3
date added to LUP
2016-04-11 15:19:56
date last changed
2016-10-13 05:05:54
@misc{815cf627-0598-4750-8055-67f2c5ac89a3,
  abstract     = {<p>Apoptosis is an active process that plays a key role in many physiological and pathological conditions. One of the most important organelles involved in apoptosis regulation is the mitochondrion. An increase in intracellular Ca(2+) is a general mechanism of toxicity in neurons which occurs in response to different noxious stimuli like excitotoxicity and ischemia producing apoptotic and necrotic cell death through mitochondria-dependent mechanisms. The Bcl-2 family of proteins modulate the release of pro-apoptotic factors from the mitochondrial intermembrane space during cell death induction by different stimuli. In this work, we have studied, using single-cell imaging and patch-clamp single channel recording, the mitochondrial mechanisms involved in the neuroprotective effect of Bcl-x(L) on Ca(2+) overload-mediated cell death in human neuroblastoma SH-SY5Y cells. We have found that Bcl-x(L) neuroprotective actions take place at mitochondria where this antiapoptotic protein delays both mitochondrial potential collapse and opening of the permeability transition pore by preventing Ca(2+)-mediated mitochondrial multiple conductance channel opening. Bcl-x(L) neuroprotective actions were antagonized by the Bcl-x(L) inhibitor ABT-737 and potentiated by the Ca(2+) chelator BAPTA-AM. As a consequence, this would prevent free radical production, mitochondrial membrane permeabilization, release from mitochondria of pro-apoptotic molecules, caspase activation and cellular death.</p>},
  author       = {Tornero, Daniel and Posadas, Inmaculada and Ceña, Valentín},
  issn         = {1932-6203},
  keyword      = {Apoptosis,Biological Transport,Biphenyl Compounds,Calcium,Caspases,Cell Line, Tumor,Egtazic Acid,Gene Expression Regulation,Humans,Ion Channel Gating,Ion Channels,Ionomycin,Membrane Potential, Mitochondrial,Mitochondria,Mitochondrial Membranes,Nitrophenols,Patch-Clamp Techniques,Permeability,Piperazines,Single-Cell Analysis,Sulfonamides,bcl-X Protein},
  language     = {eng},
  number       = {6},
  pages        = {20423--20423},
  publisher    = {ARRAY(0xb4f2fa8)},
  series       = {PLoS One},
  title        = {Bcl-x(L) blocks a mitochondrial inner membrane channel and prevents Ca2+ overload-mediated cell death},
  url          = {http://dx.doi.org/10.1371/journal.pone.0020423},
  volume       = {6},
  year         = {2011},
}