title: Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice.
abstract: 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. DOI:http://dx.doi.org/10.7554/eLife.00772.001.
authors.affiliation: Department of Pediatrics , Cincinnati Children's Hospital Medical Center, University of Cincinnati , Cincinnati , United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Karch
authors.forename: Jennifer Q
authors.initials: JQ
authors.lastname: Kwong
authors.forename: Adam R
authors.initials: AR
authors.lastname: Burr
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sargent
authors.forename: John W
authors.initials: JW
authors.lastname: Elrod
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Peixoto
authors.forename: Sonia
authors.initials: S
authors.lastname: Martinez-Caballero
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: Emily H-Y
authors.initials: EH
authors.lastname: Cheng
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Kathleen W
authors.initials: KW
authors.lastname: Kinnally
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D000083162:Mitochondrial Permeability Transition Pore; D009336:Necrosis; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000502:physiology*
chemical_list: C494827:Bax protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
keywords: Mouse; cell death; mitochondria; necrosis