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The FEBS Journal Feb 2018Bax 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... (Review)
Review
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.
Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Dimerization; Humans; Lipid Bilayers; Lipid Mobilization; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Models, Biological; Porosity; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization; Proto-Oncogene Proteins c-bcl-2; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 28755482
DOI: 10.1111/febs.14186 -
Molecular Cell Mar 2022BAX and BAK are key apoptosis regulators that mediate the decisive step of mitochondrial outer membrane permeabilization. However, the mechanism by which they assemble...
BAX and BAK are key apoptosis regulators that mediate the decisive step of mitochondrial outer membrane permeabilization. However, the mechanism by which they assemble the apoptotic pore remains obscure. Here, we report that BAX and BAK present distinct oligomerization properties, with BAK organizing into smaller structures with faster kinetics than BAX. BAK recruits and accelerates BAX assembly into oligomers that continue to grow during apoptosis. As a result, BAX and BAK regulate each other as they co-assemble into the same apoptotic pores, which we visualize. The relative availability of BAX and BAK molecules thereby determines the growth rate of the apoptotic pore and the relative kinetics by which mitochondrial contents, most notably mtDNA, are released. This feature of BAX and BAK results in distinct activation kinetics of the cGAS/STING pathway with implications for mtDNA-mediated paracrine inflammatory signaling.
Topics: Animals; Apoptosis; Cell Line, Tumor; DNA, Mitochondrial; Humans; Inflammation; Mitochondria; Protein Multimerization; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 35120587
DOI: 10.1016/j.molcel.2022.01.008 -
Immunity Mar 2022Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced...
Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced death that requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity, which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptotic caspase-8 substrate BID was dispensable for BAX and BAK activation. Instead, caspase-8 reduced pro-survival BCL-2 transcription and increased inducible nitric oxide synthase (iNOS), thus facilitating BAX and BAK signaling. IFNγ-primed, TLR-induced macrophage killing required iNOS, which licensed apoptotic caspase-8 activity and reduced the BAX and BAK inhibitors, A1 and MCL-1. The deletion of iNOS or caspase-8 limited SARS-CoV-2-induced disease in mice, while caspase-8 caused lethality independent of iNOS in a model of hemophagocytic lymphohistiocytosis. These findings reveal that iNOS selectively licenses programmed cell death, which may explain how nitric oxide impacts disease severity in SARS-CoV-2 infection and other iNOS-associated inflammatory conditions.
Topics: Animals; COVID-19; Caspase 8; Cells, Cultured; Cytotoxicity, Immunologic; Humans; Interferon-gamma; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Nitric Oxide Synthase Type II; Pathogen-Associated Molecular Pattern Molecules; SARS-CoV-2; Signal Transduction; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 35139355
DOI: 10.1016/j.immuni.2022.01.003 -
Cell Jul 2006Mitochondria amplify activation of caspases during apoptosis by releasing cytochrome c and other cofactors. This is accompanied by fragmentation of the organelle and...
Mitochondria amplify activation of caspases during apoptosis by releasing cytochrome c and other cofactors. This is accompanied by fragmentation of the organelle and remodeling of the cristae. Here we provide evidence that Optic Atrophy 1 (OPA1), a profusion dynamin-related protein of the inner mitochondrial membrane mutated in dominant optic atrophy, protects from apoptosis by preventing cytochrome c release independently from mitochondrial fusion. OPA1 does not interfere with activation of the mitochondrial "gatekeepers" BAX and BAK, but it controls the shape of mitochondrial cristae, keeping their junctions tight during apoptosis. Tightness of cristae junctions correlates with oligomerization of two forms of OPA1, a soluble, intermembrane space and an integral inner membrane one. The proapoptotic BCL-2 family member BID, which widens cristae junctions, also disrupts OPA1 oligomers. Thus, OPA1 has genetically and molecularly distinct functions in mitochondrial fusion and in cristae remodeling during apoptosis.
Topics: Animals; Apoptosis; Cell Line; GTP Phosphohydrolases; Membrane Fusion; Mice; Mice, Knockout; Mitochondria; Mitochondrial Membranes; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tight Junctions; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 16839885
DOI: 10.1016/j.cell.2006.06.025 -
Biochemical Society Transactions Jun 2022Apoptosis is a common cell death program that is important in human health and disease. Signaling in apoptosis is largely driven through protein-protein interactions.... (Review)
Review
Apoptosis is a common cell death program that is important in human health and disease. Signaling in apoptosis is largely driven through protein-protein interactions. The BCL-2 family proteins function in protein-protein interactions as key regulators of mitochondrial poration, the process that initiates apoptosis through the release of cytochrome c, which activates the apoptotic caspase cascade leading to cellular demolition. The BCL-2 pore-forming proteins BAK and BAX are the key executors of mitochondrial poration. We review the state of knowledge of protein-protein and protein-lipid interactions governing the apoptotic function of BAK and BAX, as determined through X-ray crystallography and NMR spectroscopy studies. BAK and BAX are dormant, globular α-helical proteins that participate in protein-protein interactions with other pro-death BCL-2 family proteins, transforming them into active, partially unfolded proteins that dimerize and associate with and permeabilize mitochondrial membranes. We compare the protein-protein interactions observed in high-resolution structures with those derived in silico by AlphaFold, making predictions based on combining experimental and in silico approaches to delineate the structural basis for novel protein-protein interaction complexes of BCL-2 family proteins.
Topics: Apoptosis; Humans; Lipids; Proto-Oncogene Proteins c-bcl-2; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 35521828
DOI: 10.1042/BST20220323 -
Trends in Cell Biology Apr 2017Bax and its homolog Bak are key regulators of the mitochondrial pathway of apoptosis. On cell stress Bax and Bak accumulate at distinct foci on the mitochondrial surface... (Review)
Review
Bax and its homolog Bak are key regulators of the mitochondrial pathway of apoptosis. On cell stress Bax and Bak accumulate at distinct foci on the mitochondrial surface where they undergo a conformational change, oligomerize, and mediate cytochrome c release, leading to cell death. The molecular mechanisms of Bax and Bak assembly and mitochondrial permeabilization have remained a longstanding question in the field. Recent structural and biophysical studies at several length scales have shed light on key aspects of Bax and Bak function that have shifted how we think this process occurs. These discoveries reveal an unexpected molecular mechanism in which Bax (and likely Bak) dimers assemble into oligomers with an even number of molecules that fully or partially delineate pores of different sizes to permeabilize the mitochondrial outer membrane (MOM) during apoptosis.
Topics: Animals; Apoptosis; Humans; Mitochondria; Models, Biological; Protein Multimerization; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 27932064
DOI: 10.1016/j.tcb.2016.11.004 -
Trends in Cell Biology Dec 2016Cellular commitment to the mitochondrial pathway of apoptosis is accomplished when proapoptotic B cell chronic lymphocytic leukemia/lymphoma (BCL)-2 proteins compromise... (Review)
Review
Cellular commitment to the mitochondrial pathway of apoptosis is accomplished when proapoptotic B cell chronic lymphocytic leukemia/lymphoma (BCL)-2 proteins compromise mitochondrial integrity through the process of mitochondrial outer membrane permeabilization (MOMP). For nearly three decades, intensive efforts focused on the identification and interactions of two key proapoptotic BCL-2 proteins: BCL-2 antagonist killer (BAK) and BCL-2-associated X (BAX). Indeed, we now have critical insights into which BCL-2 proteins interact with BAK/BAX to either preserve survival or initiate MOMP. In contrast, while mitochondria are targeted by BAK/BAX, a molecular understanding of how these organelles govern BAK/BAX function remains less clear. Here, we integrate recent mechanistic insights of proapoptotic BCL-2 protein function in the context of mitochondrial environment, and discuss current and potential pharmacological opportunities to control MOMP in disease.
Topics: Amino Acid Sequence; Animals; Apoptosis; Humans; Membrane Potential, Mitochondrial; Mitochondria; Models, Biological; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 27498846
DOI: 10.1016/j.tcb.2016.07.002 -
Biochimica Et Biophysica Acta.... Oct 2022In multicellular organisms the regulated cell death apoptosis is critically important for both ontogeny and homeostasis. Mitochondria are indispensable for... (Review)
Review
In multicellular organisms the regulated cell death apoptosis is critically important for both ontogeny and homeostasis. Mitochondria are indispensable for stress-induced apoptosis. The BCL-2 protein family controls mitochondrial apoptosis and initiates cell death through the pro-apoptotic activities of BAX and BAK at the outer mitochondrial membrane (OMM). Cellular survival is ensured by the retrotranslocation of mitochondrial BAX and BAK into the cytosol by anti-apoptotic BCL-2 proteins. BAX/BAK-dependent OMM permeabilization releases the mitochondrial cytochrome c (cyt c), which initiates activation of caspase-9. The caspase cascade leads to cell shrinkage, plasma membrane blebbing, chromatin condensation, and apoptotic body formation. Although it is clear that ultimately complexes of active BAX and BAK commit the cell to apoptosis, the nature of these complexes is still enigmatic. Excessive research has described a range of complexes, varying from a few molecules to several 10,000, in different systems. BAX/BAK complexes potentially form ring-like structures that could expose the inner mitochondrial membrane. It has been suggested that these pores allow the efflux of small proteins and even mitochondrial DNA. Here we summarize the current state of knowledge for mitochondrial BAX/BAK complexes and the interactions between these proteins and the membrane.
Topics: Apoptosis Regulatory Proteins; Mitochondria; Mitochondrial Membranes; Proto-Oncogene Proteins c-bcl-2; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 35752202
DOI: 10.1016/j.bbamcr.2022.119317 -
Biomolecules Dec 2020BOK is an evolutionarily conserved BCL-2 family member that resembles the apoptotic effectors BAK and BAX in sequence and structure. Based on these similarities, BOK has... (Review)
Review
BOK is an evolutionarily conserved BCL-2 family member that resembles the apoptotic effectors BAK and BAX in sequence and structure. Based on these similarities, BOK has traditionally been classified as a BAX-like pro-apoptotic protein. However, the mechanism of action and cellular functions of BOK remains controversial. While some studies propose that BOK could replace BAK and BAX to elicit apoptosis, others attribute to this protein an indirect way of apoptosis regulation. Adding to the debate, BOK has been associated with a plethora of non-apoptotic functions that makes this protein unpredictable when dictating cell fate. Here, we compile the current knowledge and open questions about this paradoxical protein with a special focus on its structural features as the key aspect to understand BOK biological functions.
Topics: Amino Acid Sequence; Animals; Apoptosis; Calcium; Eukaryotic Cells; Gene Expression Regulation; Humans; Mitochondria; Mitochondrial Membranes; Models, Molecular; Permeability; Protein Conformation; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Uridine; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 33291826
DOI: 10.3390/biom10121638 -
Biochimica Et Biophysica Acta.... Dec 2021Mitochondrial outer membrane permeabilization (MOMP) is a key checkpoint in apoptosis that activates the caspase cascade and irreversibly causes the majority of cells to... (Review)
Review
Mitochondrial outer membrane permeabilization (MOMP) is a key checkpoint in apoptosis that activates the caspase cascade and irreversibly causes the majority of cells to die. The proteins of the Bcl-2 family are master regulators of apoptosis that form a complex interaction network within the mitochondrial membrane that determines the induction of MOMP. This culminates in the activation of the effector members Bax and Bak, which permeabilize the mitochondrial outer membrane to mediate MOMP. Although the key role of Bax and Bak has been established, many questions remain unresolved regarding molecular mechanisms that control the apoptotic pore. In this review, we discuss the recent progress in our understanding of the regulation of Bax/Bak activity within the mitochondrial membrane.
Topics: Apoptosis; Caspases; Humans; Mitochondria; Mitochondrial Membranes; Permeability; Proto-Oncogene Proteins c-bcl-2; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 34343535
DOI: 10.1016/j.bbamem.2021.183716