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Bcl-2 And Bax Regulate The Channel Activity Of The Mitochondrial Adenine Nucleotide Translocator

C. Brenner, H. Cadiou, H. Vieira, N. Zamzami, I. Marzo, Z. Xie, B. Leber, D. Andrews, H. Duclohier, John Calvin Reed, G. Kroemer
Published 2000 · Medicine, Biology

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Bcl-2 family protein including anti-apoptotic (Bcl-2) or pro-apoptotic (Bax) members can form ion channels when incorporated into synthetic lipid bilayers. This contrasts with the observation that Bcl-2 stabilizes the mitochondrial membrane barrier function and inhibits the permeability transition pore complex (PTPC). Here we provide experimental data which may explain this apparent paradox. Bax and adenine nucleotide translocator (ANT), the most abundant inner mitochondrial membrane protein, can interact in artificial lipid bilayers to yield an efficient composite channel whose electrophysiological properties differ quantitatively and qualitatively from the channels formed by Bax or ANT alone. The formation of this composite channel can be observed in conditions in which Bax protein alone has no detectable channel activity. Cooperative channel formation by Bax and ANT is stimulated by the ANT ligand atractyloside (Atr) but inhibited by ATP, indicating that it depends on the conformation of ANT. In contrast to the combination of Bax and ANT, ANT does not form active channels when incorporated into membranes with Bcl-2. Rather, ANT and Bcl-2 exhibit mutual inhibition of channel formation. Bcl-2 prevents channel formation by Atr-treated ANT and neutralizes the cooperation between Bax and ANT. Our data are compatible with a ménage à trois model of mitochondrial apoptosis regulation in which ANT, the likely pore forming protein within the PTPC, interacts with Bax or Bcl-2 which influence its pore forming potential in opposing manners.
This paper references
10.1021/BI960833V
Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+.
N. Brustovetsky (1996)
Meth. Enzymol
Sa Susin (1999)
Cell Death Di?er
R. Clem (1996)
Am
HG (1994)
10.1038/385353A0
Bcl-xL forms an ion channel in synthetic lipid membranes
A. Minn (1997)
10.1073/PNAS.94.21.11357
Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2.
P. Schlesinger (1997)
10.1073/PNAS.95.9.4997
Bax directly induces release of cytochrome c from isolated mitochondria.
J. Jürgensmeier (1998)
10.1136/bmj.1.4959.155-a
Biochemistry
F. G. Young (1955)
Eur
H. Duclohier (1994)
Proc. Natl. Acad. Sci. USA
Ph Schlesinger (1997)
10.1021/BI973052I
Acidic pH promotes dimerization of Bcl-2 family proteins.
Z. Xie (1998)
10.1042/BJ3360287
Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition.
K. Woodfield (1998)
Eur
M Crompton (1998)
10.1073/PNAS.95.25.14681
Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria.
M. Narita (1998)
10.1016/S0092-8674(00)80450-X
Bcl-xL Regulates the Membrane Potential and Volume Homeostasis of Mitochondria
M. V. Heiden (1997)
10.1146/ANNUREV.PHYSIOL.60.1.619
The mitochondrial death/life regulator in apoptosis and necrosis.
G. Kroemer (1998)
Selective permeability versus independence
B. Hille (1984)
Annu. Rev. Physiol
G Kroemer (1998)
10.1038/NM0697-614
The proto-oncogene Bcl-2 and its role in regulating apoptosis
G. Kroemer (1997)
Biochem. J
K Wood®eld (1998)
10.1084/JEM.189.2.381
Mitochondrial Release of Caspase-2 and -9 during the Apoptotic Process
S. Susin (1999)
Cancer Res
S Krajewski (1993)
Eur. Biophys. J
M Brullemans (1994)
10.1016/S0092-8674(00)80085-9
Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome c
X. Liu (1996)
Eur. J. Biochem
M Crompton (1998)
Proc. Natl. Acad. Sci. USA, 95
Jm Juè Rgensmeier (1998)
10.1515/9783111576855-015
J
Seguin Hen (1824)
10.1084/JEM.183.4.1533
Mitochondrial control of nuclear apoptosis
N. Zamzami (1996)
10.1084/JEM.187.8.1261
The Permeability Transition Pore Complex: A Target for Apoptosis Regulation by Caspases and Bcl-2–related Proteins
I. Marzo (1998)
Bioelectrochem. Bioenerg
W Hanke (1984)
10.1007/BF00192204
Implication of segment S45 in the permeation pathway of voltage-dependent sodium channels
M. Brullemans (2004)
Proc
S Schendel (1997)
Selective permeability versus independence In: Ionic channels of excitable membranes
B Hille (1984)
10.1038/369321A0
BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax
X. Yin (1994)
Proc. Natl. Acad. Sci. USA
M Montal (1972)
Am. J. Pathol
S Krajewski (1994)
Bioelectrochem
W Hanke (1984)
J. Exp. Med
I Marzo (1998)
Meth
SA Susin (1999)
10.1016/0092-8674(93)90509-O
Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death
Zoltán N. Oltval (1993)
10.1038/NG0897-358
Bcl-2 and Bax function independently to regulate cell death
C. Knudson (1997)
10.1126/SCIENCE.281.5381.1309
Mitochondria and apoptosis.
D. Green (1998)
10.1073/PNAS.69.12.3561
Formation of bimolecular membranes from lipid monolayers and a study of their electrical properties.
M. Montal (1972)
Nat. Gen
Cm Knudson (1997)
Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2.
S. Krajewski (1994)
10.1038/17135
Molecular characterization of mitochondrial apoptosis-inducing factor
S. Susin (1999)
Proc
PH Schlesinger (1997)
J. Exp. Med
10.1073/PNAS.94.10.5113
Channel formation by antiapoptotic protein Bcl-2.
S. Schendel (1997)
Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes.
S. Krajewski (1993)
10.1016/S0014-5793(00)01734-8
FEBS Lett
M. Saraste (2000)
10.1016/0092-8674(94)90188-0
Checkpoints of dueling dimers foil death wishes
Z. Oltvai (1994)
10.1002/j.1460-2075.1996.tb00788.x
Bcl‐2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types.
W. Zhu (1996)
10.1016/0092-8674(93)90586-F
Cell
AC Tose (1993)
10.1084/JEM.184.4.1331
Bcl-2 inhibits the mitochondrial release of an apoptogenic protease
S. Susin (1996)
10.1074/JBC.271.4.2185
Interactions of Cyclophilin with the Mitochondrial Inner Membrane and Regulation of the Permeability Transition Pore, a Cyclosporin A-sensitive Channel (*)
A. Nicolli (1996)
J. Biol. Chem
A Nicolli (1996)
10.1016/0302-4598(84)87013-0
Ion channel reconstitution into lipid bilayer membranes on glass patch pipettes
W. Hanke (1984)
Electrophysiology of ANT/Bcl-2 and ANT/Bax interactions C Brenner et al
Proc
S Shimizu (1998)
J. Exp. Med
Sa Susin (1999)
EMBO J
W Zhu (1996)
J. Biol. Chem
S Matsuyama (1998)
10.1046/J.1432-1327.1998.2580729.X
Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore.
M. Crompton (1998)
10.1073/PNAS.95.4.1455
Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux.
S. Shimizu (1998)
Proc
M Narita (1998)
Proc
M Montal (1972)
10.1074/jbc.273.47.30995
Cytoprotection by Bcl-2 Requires the Pore-forming α5 and α6 Helices*
S. Matsuyama (1998)
10.1083/JCB.140.6.1485
The Caspase-3 Precursor Has a Cytosolic and Mitochondrial Distribution: Implications for Apoptotic Signaling
M. Mancini (1998)
Nat
CM Knudson (1997)
Proc. Natl. Acad. Sci. USA, 95
M Narita (1998)
Proc. Natl. Acad. Sci. USA, 95
S Shimizu (1998)
10.1021/BI960840J
Peroxidative modification of a membrane protein. Conformation-dependent chemical modification of adenine nucleotide translocase in Cu2+/tert-butyl hydroperoxide treated mitochondria.
J. Girón-Calle (1996)
10.1016/S0014-5793(98)00317-2
Reconstituted adenine nucleotide translocase forms a channel for small molecules comparable to the mitochondrial permeability transition pore
A. Rück (1998)
Proc. Natl. Acad. Sci. USA
S Schendel (1997)
J. Cell Biol
J. Exp. Med
N Zamzami (1996)
10.1038/sj.cdd.4400365
Bcl-2 family proteins as ion-channels
S. Schendel (1998)



This paper is referenced by
10.1002/jcb.22869
Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: The cellular mechanism
Ning Wang (2010)
MINIREVIEW Adenine Nucleotide Translocator in Heart
M. Portman (2000)
10.1038/sj.cdd.4401006
Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization
P. Boya (2002)
10.1016/J.BBAMCR.2003.11.001
Viral Bcl-2 homologs and their role in virus replication and associated diseases.
B. Polster (2004)
10.1016/j.mito.2008.10.003
Putative partners in Bax mediated cytochrome-c release: ANT, CypD, VDAC or none of them?
R. Kumarswamy (2009)
10.1007/978-1-4419-9530-8_7
Caspase-Independent Stroke Targets
Ruoyang Shi (2012)
10.1007/s12011-016-0701-8
Alleviation of Lead-Induced Apoptosis by Puerarin via Inhibiting Mitochondrial Permeability Transition Pore Opening in Primary Cultures of Rat Proximal Tubular Cells
Zhong-Kun Wang (2016)
10.1111/jnc.13900
The regulator of calcineurin 1 increases adenine nucleotide translocator 1 and leads to mitochondrial dysfunctions
H. Jiang (2017)
10.1038/nrm2970
Molecular mechanisms of necroptosis: an ordered cellular explosion
P. Vandenabeele (2010)
10.1038/35048073
The mitochondrion in apoptosis: how Pandora's box opens
N. Zamzami (2001)
Aspects moléculaires et cellulaires de l'activité cytotoxique de la mitogaligine, une protéine inductrice de la mort cellulaire.
P. González (2007)
10.1016/j.biocel.2009.12.024
The fourth isoform of the adenine nucleotide translocator inhibits mitochondrial apoptosis in cancer cells.
Cindy Gallerne (2010)
10.1046/J.1365-2184.2003.00286.X
The presence of 19-kDa Bcl-2 in dividing cells.
R. W. Hoetelmans (2003)
Translation and transcription: the dual functionality of LysRS in mast cells.
Nurit Yannay-Cohen (2006)
Bcl-2 and Bax Modulate Adenine Nucleotide Translocase Activity 1
Anne-Sophie Belzacq (2003)
10.3389/fonc.2012.00077
The splicing mutant of the human tumor suppressor protein DFNA5 induces programmed cell death when expressed in the yeast Saccharomyces cerevisiae
Sofie Van Rossom (2012)
10.1159/000046878
Mitochondrial Creatine Kinase in Contact Sites: Interaction with Porin and Adenine Nucleotide Translocase, Role in Permeability Transition and Sensitivity to Oxidative Damage
M. Dolder (2001)
10.1161/01.RES.87.4.328
Host Gene Regulation During Coxsackievirus B3 Infection in Mice: Assessment by Microarrays
L. Taylor (2000)
10.1016/j.scitotenv.2018.09.313
Hepatorenal protective effects of taurine and N-acetylcysteine against fipronil-induced injuries: The antioxidant status and apoptotic markers expression in rats.
M. Abdel-Daim (2019)
10.1016/S0733-8651(05)70195-8
Antiapoptotic proteins. The bcl-2 and inhibitor of apoptosis protein families.
Q. Deveraux (2001)
10.1074/jbc.M306021200
Bcl-XL Mutations Suppress Cellular Sensitivity to Antimycin A*
M. Manion (2004)
10.1016/S0169-409X(01)00123-5
Mitochondria make a come back.
I. Scheffler (2001)
10.1213/01.ane.0000278083.31991.36
Noble Gases Without Anesthetic Properties Protect Myocardium Against Infarction by Activating Prosurvival Signaling Kinases and Inhibiting Mitochondrial Permeability Transition In Vivo
P. Pagel (2007)
10.1089/neu.2008.0538
Hyperbaric oxygen preconditioning attenuates early apoptosis after spinal cord ischemia in rats.
L. Wang (2009)
10.1089/ars.2009.2607
Aberrant reactive oxygen and nitrogen species generation in rheumatoid arthritis (RA): causes and consequences for immune function, cell survival, and therapeutic intervention.
D. Phillips (2010)
10.18297/etd/155
Mitochondrial targeting of the pro-apoptotic protein Bax : Role of the Bax carboxy-terminal tail.
S. Brock (2009)
Hepatoprotective Activity and Inhibitory Effect of Flavonoid -Rich Extract of Brysocarpus Coccineus Leaves on Mitochondrial Membrane Permeability Transition Pore
O. Adedosu (2014)
10.1073/pnas.1217823110
Dimers of mitochondrial ATP synthase form the permeability transition pore
V. Giorgio (2013)
10.1006/EXCR.2000.4833
The mitochondrion in cell death control: certainties and incognita.
M. Loeffler (2000)
10.1016/S0005-2728(02)00213-X
Bcl-2 protects against apoptosis induced by antimycin A and bongkrekic acid without restoring cellular ATP levels.
A. O. de Graaf (2002)
10.1152/AJPRENAL.00301.2001
Mitochondrial dysfunction is an early event in high-NaCl-induced apoptosis of mIMCD3 cells.
L. Michea (2002)
10.1038/sj.onc.1208001
Dynamic evolution of the adenine nucleotide translocase interactome during chemotherapy-induced apoptosis
F. Verrier (2004)
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