Abstract
Bax and Bak are members of the Bcl-2 family and core regulators of the intrinsic pathway of apoptosis. Upon apoptotic stimuli, they are activated and oligomerize at the mitochondrial outer membrane (MOM) to mediate its permeabilization, which is considered a key step in apoptosis. However, the molecular mechanism underlying Bax and Bak function has remained a key question in the field. Here, we review recent structural and biophysical evidence that has changed our understanding of how Bax and Bak promote MOM permeabilization. We also discuss how the spatial regulation of Bcl-2 family preference for binding partners contributes to regulate Bax and Bak activation. Finally, we consider the contribution of mitochondrial composition, dynamics and interaction with other organelles to apoptosis commitment. A new perspective is emerging, in which the control of apoptosis by Bax and Bak goes beyond them and is highly influenced by additional mitochondrial components.
Keywords:
BAK; BAX; BCL-2 family; DRP1; apoptosis; mitochondria; mitochondrial outer membrane permeabilization.
© 2017 Federation of European Biochemical Societies.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / agonists
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Apoptosis Regulatory Proteins / chemistry
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Apoptosis Regulatory Proteins / metabolism*
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Apoptosis*
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Dimerization
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Humans
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Lipid Bilayers / chemistry
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Lipid Bilayers / metabolism
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Lipid Mobilization
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Mitochondria / chemistry
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Mitochondria / enzymology
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Mitochondria / metabolism
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Mitochondrial Dynamics*
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Membranes / chemistry
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Mitochondrial Membranes / enzymology
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Mitochondrial Membranes / metabolism*
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Models, Biological*
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Porosity
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Protein Conformation
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Protein Interaction Domains and Motifs
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Protein Multimerization
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Proto-Oncogene Proteins c-bcl-2 / agonists
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Proto-Oncogene Proteins c-bcl-2 / chemistry
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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bcl-2 Homologous Antagonist-Killer Protein / agonists
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bcl-2 Homologous Antagonist-Killer Protein / chemistry
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2-Associated X Protein / agonists
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bcl-2-Associated X Protein / chemistry
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bcl-2-Associated X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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BAK1 protein, human
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BAX protein, human
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Lipid Bilayers
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Mitochondrial Membrane Transport Proteins
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Proto-Oncogene Proteins c-bcl-2
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RTL10 protein, human
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein