Mitochondrial Shape Governs BAX-Induced Membrane Permeabilization and Apoptosis

被引：170

作者：

Renault, Thibaud T. ^{[1
,2
,3
]}

Floros, Konstantinos V. ^{[1
,2
]}

Elkholi, Rana ^{[1
,2
,4
]}

Corrigan, Kelly-Ann ^{[1
]}

Kushnareva, Yulia ^{[5
]}

Wieder, Shira Y. ^{[1
,6
]}

Lindtner, Claudia ^{[7
]}

Serasinghe, Madhavika N. ^{[1
,2
,3
,6
]}

Asciolla, James J. ^{[1
,2
,6
]}

Buettner, Christoph ^{[3
,7
,8
]}

Newmeyer, Donald D. ^{[5
]}

Chipuk, Jerry E. ^{[1
,2
,3
,4
,6
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Diabet Obes & Metab Inst, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY 10029 USA

[5] La Jolla Inst Allergy & Immunol, Div Immune Regulat, La Jolla, CA 92037 USA

[6] Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA

[7] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA

[8] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA

来源：

MOLECULAR CELL | 2015年 / 57卷 / 01期

关键词：

UNFOLDED PROTEIN RESPONSE; BCL-2; FAMILY-MEMBERS; OUTER-MEMBRANE; ENDOPLASMIC-RETICULUM; GENE-EXPRESSION; BH3; DOMAINS; CELL-DEATH; STRESS; ER; INDUCTION;

D O I：

10.1016/j.molcel.2014.10.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Proapoptotic BCL-2 proteins converge upon the outer mitochondrial membrane (OMM) to promote mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Here we investigated the mechanistic relationship between mitochondrial shape and MOMP and provide evidence that BAX requires a distinct mitochondrial size to induce MOMP. We utilized the terminal unfolded protein response pathway to systematically define proapoptotic BCL-2 protein composition after stress and then directly interrogated their requirement for a productive mitochondrial size. Complementary biochemical, cellular, in vivo, and ex vivo studies reveal that Mfn1, aGTPase involved in mitochondrial fusion, establishes a mitochondrial size that is permissive for proapoptotic BCL-2 family function. Cells with hyperfragmented mitochondria, along with size-restricted OMM model systems, fail to support BAX-dependent membrane association and permeabilization due to an inability to stabilize BAX alpha 9.membrane interactions. This work identifies a mechanistic contribution of mitochondrial size in dictating BAX activation, MOMP, and apoptosis.

引用

页码：69 / 82

页数：14

共 48 条

[1] Examining BCL-2 Family Function with Large Unilamellar Vesicles [J].

Asciolla, James J. ;

Renault, Thibaud T. ;

Chipuk, Jerry E. .

JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, 2012, (68)

[2] BAK activation is necessary and sufficient to drive ceramide synthase-dependent ceramide accumulation following inhibition of BCL2-like proteins [J].

Beverly, Levi J. ;

Howell, Lauren A. ;

Hernandez-Corbacho, Maria ;

Casson, Lavona ;

Chipuk, Jerry E. ;

Siskind, Leah J. .

BIOCHEMICAL JOURNAL, 2013, 452 :111-119

[3] Protein targeting [J].

Blobel, G .

BIOSCIENCE REPORTS, 2000, 20 (05) :303-344

[4] Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization [J].

Cassidy-Stone, Ann ;

Chipuk, Jerry E. ;

Ingerman', Elena ;

Song, Cheng ;

Yoo, Choong ;

Kuwana, Tomomi ;

Kurth, Mark J. ;

Shaw, Jared T. ;

Hinshaw, Jenny E. ;

Green, Douglas R. ;

Nunnari, Jodi .

DEVELOPMENTAL CELL, 2008, 14 (02) :193-204

[5] Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members [J].

Certo, Michael ;

Moore, Victoria Del Gaizo ;

Nishino, Mari ;

Wei, Guo ;

Korsmeyer, Stanley ;

Armstrong, Scott A. ;

Letai, Anthony .

CANCER CELL, 2006, 9 (05) :351-365

[6] Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development [J].

Chen, HC ;

Detmer, SA ;

Ewald, AJ ;

Griffin, EE ;

Fraser, SE ;

Chan, DC .

JOURNAL OF CELL BIOLOGY, 2003, 160 (02) :189-200

[7] Sphingolipid Metabolism Cooperates with BAK and BAX to Promote the Mitochondrial Pathway of Apoptosis [J].

Chipuk, Jerry E. ;

McStay, Gavin P. ;

Bharti, Archana ;

Kuwana, Tomomi ;

Clarke, Christopher J. ;

Siskind, Leah J. ;

Obeid, Lina M. ;

Green, Douglas R. .

CELL, 2012, 148 (05) :988-1000

[8] The BCL-2 Family Reunion [J].

Chipuk, Jerry E. ;

Moldoveanu, Tudor ;

Llambi, Fabien ;

Parsons, Melissa J. ;

Green, Douglas R. .

MOLECULAR CELL, 2010, 37 (03) :299-310

[9] Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins [J].

Chipuk, Jerry E. ;

Fisher, John C. ;

Dillon, Christopher P. ;

Kriwacki, Richard W. ;

Kuwana, Tomomi ;

Green, Douglas R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (51) :20327-20332

[10] Mitochondrial Cristae Shape Determines Respiratory Chain Supercomplexes Assembly and Respiratory Efficiency [J].

Cogliati, Sara ;

Frezza, Christian ;

Soriano, Maria Eugenia ;

Varanita, Tatiana ;

Quintana-Cabrera, Ruben ;

Corrado, Mauro ;

Cipolat, Sara ;

Costa, Veronica ;

Casarin, Alberto ;

Gomes, Ligia C. ;

Perales-Clemente, Ester ;

Salviati, Leonardo ;

Fernandez-Silva, Patricio ;

Enriquez, Jose A. ;

Scorrano, Luca .

CELL, 2013, 155 (01) :160-171

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