Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice
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
Affiliations
Jason Karch
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States
Jennifer Q Kwong
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States
Adam R Burr
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States
Michelle A Sargent
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States
John W Elrod
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States
Pablo M Peixoto
Department of Basic Sciences, New York University College of Dentistry, New York, United States
Sonia Martinez-Caballero
Department of Basic Sciences, New York University College of Dentistry, New York, United States
Hanna Osinska
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States
Emily H-Y Cheng
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States
Jeffrey Robbins
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States
Kathleen W Kinnally
Department of Basic Sciences, New York University College of Dentistry, New York, United States
Jeffery D Molkentin
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, United States; Howard Hughes Medical Institute, University of Cincinnati, Cincinnati, United States
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.
