title: Regulated necrotic cell death: the passive aggressive side of Bax and Bak.
abstract: Although the molecular effectors of apoptotic cell death have been largely annotated over the past 30 years, leading to a strong biological understanding of this process and its importance in cell biology, cell death through necrosis has only recently been accepted as a similarly regulated process with definable molecular effectors. The mitochondria are important and central mediators of both apoptosis and regulated necrosis. In apoptosis, the B-cell leukemia/lymphoma 2 (Bcl-2) family members Bcl-2-associated protein x (Bax) and Bcl-2 homologues antagonist/killer (Bak) undergo oligomerization in the outer mitochondrial membrane resulting in the release of apoptosis inducing substrates and the activation of caspases and nucleases. In contrast, during necrosis the mitochondria become dysfunctional and maladaptive in conjunction with reactive oxygen species production and the loss of ATP production, in part through opening of the mitochondrial permeability transition pore. Although regulated necrosis is caspase-independent, recent evidence has shown that it still requires the apoptotic regulators Bax/Bak, which can regulate the permeability characteristics of the outer mitochondrial membrane in their nonoligomerized state. Here, we review the nonapoptotic side of Bcl-2 family, specifically the role of Bax/Bak in regulated necrotic cell death. We will also discuss how these Bcl-2 family member effectors could be part of a larger integrated network that ultimately decides the fate of a given cell somewhere within a molecular continuum between apoptosis and regulated necrosis.
authors.affiliation: From the Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, OH (J.K., J.D.M.); and Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.).
authors.forename: Jason
authors.initials: J
authors.lastname: Karch
authors.affiliation: From the Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, OH (J.K., J.D.M.); and Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.). jeff.molkentin@cchmc.org.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D009336:Necrosis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
keywords: apoptosis; calcium; mitochondria; necrosis