Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice
A critical event in ischemia-based cell death is the opening of the mitochondrial permeability transition pore (MPTP). However, the molecular identity of the components of the MPTP remains unknown. Here, we determined that the Bcl-2 family members Bax and Bak, which are central regulators of apoptot...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2013-08-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/00772 |
| _version_ | 1811180452749246464 |
|---|---|
| author | Jason Karch Jennifer Q Kwong Adam R Burr Michelle A Sargent John W Elrod Pablo M Peixoto Sonia Martinez-Caballero Hanna Osinska Emily H-Y Cheng Jeffrey Robbins Kathleen W Kinnally Jeffery D Molkentin |
| author_facet | Jason Karch Jennifer Q Kwong Adam R Burr Michelle A Sargent John W Elrod Pablo M Peixoto Sonia Martinez-Caballero Hanna Osinska Emily H-Y Cheng Jeffrey Robbins Kathleen W Kinnally Jeffery D Molkentin |
| author_sort | Jason Karch |
| collection | DOAJ |
| description | A critical event in ischemia-based cell death is the opening of the mitochondrial permeability transition pore (MPTP). However, the molecular identity of the components of the MPTP remains unknown. Here, we determined that the Bcl-2 family members Bax and Bak, which are central regulators of apoptotic cell death, are also required for mitochondrial pore-dependent necrotic cell death by facilitating outer membrane permeability of the MPTP. Loss of Bax/Bak reduced outer mitochondrial membrane permeability and conductance without altering inner membrane MPTP function, resulting in resistance to mitochondrial calcium overload and necrotic cell death. Reconstitution with mutants of Bax that cannot oligomerize and form apoptotic pores, but still enhance outer membrane permeability, permitted MPTP-dependent mitochondrial swelling and restored necrotic cell death. Our data predict that the MPTP is an inner membrane regulated process, although in the absence of Bax/Bak the outer membrane resists swelling and prevents organelle rupture to prevent cell death. |
| first_indexed | 2024-04-11T09:02:22Z |
| format | Article |
| id | doaj.art-05dd5d4356784fc28183de961bc98086 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:02:22Z |
| publishDate | 2013-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-05dd5d4356784fc28183de961bc980862022-12-22T04:32:43ZengeLife Sciences Publications LtdeLife2050-084X2013-08-01210.7554/eLife.00772Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in miceJason Karch0Jennifer Q Kwong1Adam R Burr2Michelle A Sargent3John W Elrod4Pablo M Peixoto5Sonia Martinez-Caballero6Hanna Osinska7Emily H-Y Cheng8Jeffrey Robbins9Kathleen W Kinnally10Jeffery D Molkentin11Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United StatesDepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United StatesDepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United StatesDepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United StatesDepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United StatesDepartment of Basic Sciences, New York University College of Dentistry, New York, United StatesDepartment of Basic Sciences, New York University College of Dentistry, New York, United StatesDepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United StatesHuman Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United StatesDepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United StatesDepartment of Basic Sciences, New York University College of Dentistry, New York, United StatesDepartment of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States; Howard Hughes Medical Institute, University of Cincinnati, Cincinnati, United StatesA critical event in ischemia-based cell death is the opening of the mitochondrial permeability transition pore (MPTP). However, the molecular identity of the components of the MPTP remains unknown. Here, we determined that the Bcl-2 family members Bax and Bak, which are central regulators of apoptotic cell death, are also required for mitochondrial pore-dependent necrotic cell death by facilitating outer membrane permeability of the MPTP. Loss of Bax/Bak reduced outer mitochondrial membrane permeability and conductance without altering inner membrane MPTP function, resulting in resistance to mitochondrial calcium overload and necrotic cell death. Reconstitution with mutants of Bax that cannot oligomerize and form apoptotic pores, but still enhance outer membrane permeability, permitted MPTP-dependent mitochondrial swelling and restored necrotic cell death. Our data predict that the MPTP is an inner membrane regulated process, although in the absence of Bax/Bak the outer membrane resists swelling and prevents organelle rupture to prevent cell death.https://elifesciences.org/articles/00772cell deathmitochondrianecrosis |
| spellingShingle | Jason Karch Jennifer Q Kwong Adam R Burr Michelle A Sargent John W Elrod Pablo M Peixoto Sonia Martinez-Caballero Hanna Osinska Emily H-Y Cheng Jeffrey Robbins Kathleen W Kinnally Jeffery D Molkentin Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice eLife cell death mitochondria necrosis |
| title | Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice |
| title_full | Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice |
| title_fullStr | Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice |
| title_full_unstemmed | Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice |
| title_short | Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice |
| title_sort | bax and bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice |
| topic | cell death mitochondria necrosis |
| url | https://elifesciences.org/articles/00772 |
| work_keys_str_mv | AT jasonkarch baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT jenniferqkwong baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT adamrburr baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT michelleasargent baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT johnwelrod baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT pablompeixoto baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT soniamartinezcaballero baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT hannaosinska baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT emilyhycheng baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT jeffreyrobbins baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT kathleenwkinnally baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice AT jefferydmolkentin baxandbakfunctionastheoutermembranecomponentofthemitochondrialpermeabilityporeinregulatingnecroticcelldeathinmice |