scholarly journals Pleiotropy of Bcl-2 family proteins is an ancient trait in the metazoan evolution

2019 ◽  
Author(s):  
Nikolay Popgeorgiev ◽  
Lea Jabbour ◽  
Trang Thi Minh Nguyen ◽  
Nikola Ralchev ◽  
Rudy Gadet ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Phylogenetic Analyses ◽  
Mitochondrial Outer Membrane ◽  
Calcium Fluxes ◽  
Origin And Evolution ◽  
Metazoan Evolution ◽  
Trichoplax Adhaerens ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
C Terminus ◽  
Tm Domain

ABSTRACTIn the animal kingdom, proteins of the Bcl-2 family are widely recognized as regulators of mitochondrial outer membrane permeabilization (MOMP), leading to apoptotic cell death. These proteins were recently also shown to control IP3-dependent calcium fluxes at the level of the endoplasmic reticulum (ER). However, the origin and evolution of these pleiotropic functions remain elusive. Here, we molecularly characterized the four members of the Bcl-2 family (trBcl-2L1 to -2L4) in the most primitive metazoan, namely Trichoplax adhaerens. Primary structure and phylogenetic analyses demonstrated that all four trBcl-2 homologs belong to the multidomain Bcl-2 group and presented a conserved C-terminus transmembrane (TM) domain. TrBcl-2L1 and trBcl-2L2 are highly divergent proteins clustering with the anti-apoptotic Bcl-2 members, whereas trBcl-2L3 and trBcl-2L4 were homologous to the pro-apoptotic Bax (trBax) and Bak (trBak). Interestingly, at the functional level, trBak operates as a BH3 only sensitizer repressing the anti-apoptotic activities of trBcl-2L1 and trBcl-2L2, whereas trBax leads to MOMP, similarly to the well-known indirect model of Bax activation. Finally, we found that trBcl-2L1 had a dual ER and mitochondrial subcellular localization and was able to bind to IP3R. By generating two TM domain mutants we demonstrated that trBcl-2L1 targeted to the ER was able to control IP3-dependent calcium fluxes, whereas Mito-trBcl-2L1 represses trBax-dependent MOMP, suggesting that Bcl-2 pleiotropy appeared early and was conserved throughout metazoan evolution.

scholarly journals The Role of Mitochondria in Pyroptosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Qian Li ◽  
Nengxian Shi ◽  
Chen Cai ◽  
Mingming Zhang ◽  
Jing He ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Pathological Process ◽  
Mitochondrial Outer Membrane ◽  
Therapeutic Effects ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Regulated Cell Death ◽  
Clinical Benefits ◽  
Regulate Cell Death

Pyroptosis is a recently discovered aspartic aspart-specific cysteine protease (Caspase-1/4/5/11) dependent mode of gene-regulated cell death cell death, which is represented by the rupture of cell membrane perforations and the production of proinflammatory mediaters like interleukin-18(IL-18) and interleukin-1β (IL-1β). Mitochondria also play an important role in apoptotic cell death. When it comes to apoptosis of mitochondrion, mitochondrial outer membrane permeabilization (MOMP) is commonly known to cause cell death. As a downstream pathological process of apoptotic signaling, MOMP participates in the leakage of cytochrome-c from mitochondrion to the cytosol and subsequently activate caspase proteases. Hence, targeting MOMP for the sake of manipulating cell death presents potential therapeutic effects among various types of diseases, such as autoimmune disorders, neurodegenerative diseases, and cancer. In this review, we highlights the roles and significance of mitochondria in pyroptosis to provide unexplored strategies that target the mitochondria to regulate cell death for clinical benefits.

Mechanisms of p53-dependent apoptosis

2001 ◽  
Vol 29 (6) ◽  
pp. 684-688 ◽  
Author(s):  
M. Schuler ◽  
D. R. Green
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Apoptotic Cell ◽  
Mitochondrial Outer Membrane ◽  
Caspase Activation ◽  
Caspase 9 ◽  
High Molecular Weight Complex ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Cellular Stresses ◽  
Induced Apoptosis

Cellular stresses, such as growth factor deprivation, DNA damage or oncogene expression, lead to stabilization and activation of the p53 tumour suppressor protein. Depending on the cellular context, this results in one of two different outcomes: cell cycle arrest or apoptotic cell death. Cell death induced through the p53 pathway is executed by the caspase proteinases, which, by cleaving their substrates, lead to the characteristic apoptotic phenotype. Caspase activation by p53 occurs through the release of apoptogenic factors from the mitochondria, including cytochrome c and Smac/DIABLO. Released cytochrome c allows the formation of a high-molecular weight complex, the apoptosome, which consists of the adapter protein Apaf-1 and caspase 9, which is activated following recruitment into the apoptosome. Active caspase 9 then cleaves and activates the effector caspases, such as caspases-3 and -7, which execute the death program. Released Smac/DIABLO facilitates caspase activation through repression of the IAP caspase inhibitor proteins. The release of mitochondrial apoptogenic factors is regulated by the pro- and anti-apoptotic Bcl-2 family proteins, which either induce or prevent the permeabilization of the outer mitochondrial membrane. The mechanism by which p53 signals to the Bcl-2 family proteins is unclear. It was shown that some of the pro-apoptotic family members, such as Bax, Noxa or PUMA, are transcriptional targets of p53. In addition, transcription-independent, pro-apoptotic activities of p53 have been described. The elucidation of the p53-dependent pathway, resulting in mitochondrial outer membrane permeabilization through the pro-apoptotic Bcl-2 family proteins, is a key to unveiling the mechanism of stress-induced apoptosis.

scholarly journals Mitochondrial outer membrane permeabilization at the single molecule level

2021 ◽  
Author(s):  
Shashank Dadsena ◽  
Andreas Jenner ◽  
Ana J. García-Sáez
Keyword(s):  
Cell Death ◽  
Outer Membrane ◽  
Single Molecule ◽  
Apoptotic Cell ◽  
Interaction Network ◽  
Regulatory Elements ◽  
Membrane Permeabilization ◽  
Mitochondrial Outer Membrane ◽  
Apoptotic Pathway ◽  
Mitochondrial Outer Membrane Permeabilization

AbstractApoptotic cell death is essential for development, immune function or tissue homeostasis, and its mis-regulation is linked to various diseases. Mitochondrial outer membrane permeabilization (MOMP) is a central event in the intrinsic apoptotic pathway and essential to control the execution of cell death. Here we review current concepts in regulation of MOMP focusing on the interaction network of the Bcl-2 family proteins as well as further regulatory elements influencing MOMP. As MOMP is a complex spatially and temporally controlled process, we point out the importance of single-molecule techniques to unveil processes which would be masked by ensemble measurements. We report key single-molecule studies applied to decipher the composition, assembly mechanism and structure of protein complexes involved in MOMP regulation.

scholarly journals Mitochondrial Outer Membrane Proteins Assist Bid in Bax-mediated Lipidic Pore Formation

2009 ◽  
Vol 20 (8) ◽  
pp. 2276-2285 ◽  
Author(s):  
Blanca Schafer ◽  
Joel Quispe ◽  
Vineet Choudhary ◽  
Jerry E. Chipuk ◽  
Teddy G. Ajero ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Pore Formation ◽  
Outer Membrane Proteins ◽  
Mitochondrial Outer Membrane ◽  
Outer Membranes ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
In Vitro Systems ◽  
Large Round ◽  
Key Features

Mitochondrial outer membrane permeabilization (MOMP) is a critical step in apoptosis and is regulated by Bcl-2 family proteins. In vitro systems using cardiolipin-containing liposomes have demonstrated the key features of MOMP induced by Bax and cleaved Bid; however, the nature of the “pores” and how they are formed remain obscure. We found that mitochondrial outer membranes contained very little cardiolipin, far less than that required for liposome permeabilization, despite their responsiveness to Bcl-2 family proteins. Strikingly, the incorporation of isolated mitochondrial outer membrane (MOM) proteins into liposomes lacking cardiolipin conferred responsiveness to cleaved Bid and Bax. Cardiolipin dependence was observed only when permeabilization was induced with cleaved Bid but not with Bid or Bim BH3 peptide or oligomerized Bax. Therefore, we conclude that MOM proteins specifically assist cleaved Bid in Bax-mediated permeabilization. Cryoelectron microscopy of cardiolipin-liposomes revealed that cleaved Bid and Bax produced large round holes with diameters of 25–100 nm, suggestive of lipidic pores. In sum, we propose that activated Bax induces lipidic pore formation and that MOM proteins assist cleaved Bid in this process in the absence of cardiolipin.

scholarly journals Mosaic Genomes of the Six Major Primate Lentivirus Lineages Revealed by Phylogenetic Analyses

2003 ◽  
Vol 77 (13) ◽  
pp. 7202-7213 ◽  
Author(s):  
Marco Salemi ◽  
Tulio De Oliveira ◽  
Valerie Courgnaud ◽  
Vincent Moulton ◽  
Barbara Holland ◽  
...  
Keyword(s):  
Phylogenetic Relationships ◽  
Statistical Tests ◽  
Phylogenetic Analyses ◽  
Decomposition Analysis ◽  
Phylogeny Reconstruction ◽  
Origin And Evolution ◽  
Immunodeficiency Virus ◽  
Primate Lentiviruses ◽  
Recombinant Fragments ◽  
Clustering Patterns

ABSTRACT To clarify the origin and evolution of the primate lentiviruses (PLVs), which include human immunodeficiency virus types 1 and 2 as well as their simian relatives, simian immunodeficiency viruses (SIVs), isolated from several host species, we investigated the phylogenetic relationships among the six supposedly nonrecombinant PLV lineages for which the full genome sequences are available. Employing bootscanning as an exploratory tool, we located several regions in the PLV genome that seem to have uncertain or conflicting phylogenetic histories. Phylogeny reconstruction based on distance and maximum-likelihood algorithms followed by a number of statistical tests confirms the existence of at least five putative recombinant fragments in the PLV genome with different clustering patterns. Split decomposition analysis also shows that phylogenetic relationships among PLVs may be better represented by network-based graphs, such as the ones produced by SplitsTree. Our findings not only imply that the six so-called pure PLV lineages have in fact mosaic genomes but also make more unlikely the hypothesis of cospeciation of SIVs and their simian hosts.

scholarly journals Molecular fossils illuminate the evolution of retroviruses following a macroevolutionary transition from land to water

2021 ◽  
Vol 17 (7) ◽  
pp. e1009730
Author(s):  
Jialu Zheng ◽  
Jianhua Wang ◽  
Zhen Gong ◽  
Guan-Zhu Han
Keyword(s):  
Phylogenetic Analyses ◽  
Endogenous Retroviruses ◽  
Integration Time ◽  
Aquatic Environments ◽  
Ongoing Activity ◽  
Aquatic Life ◽  
Origin And Evolution ◽  
Molecular Fossils ◽  
Retroviral Infections

The ancestor of cetaceans underwent a macroevolutionary transition from land to water early in the Eocene Period >50 million years ago. However, little is known about how diverse retroviruses evolved during this shift from terrestrial to aquatic environments. Did retroviruses transition into water accompanying their hosts? Did retroviruses infect cetaceans through cross-species transmission after cetaceans invaded the aquatic environments? Endogenous retroviruses (ERVs) provide important molecular fossils for tracing the evolution of retroviruses during this macroevolutionary transition. Here, we use a phylogenomic approach to study the origin and evolution of ERVs in cetaceans. We identify a total of 8,724 ERVs within the genomes of 25 cetaceans, and phylogenetic analyses suggest these ERVs cluster into 315 independent lineages, each of which represents one or more independent endogenization events. We find that cetacean ERVs originated through two possible routes. 298 ERV lineages may derive from retrovirus endogenization that occurred before or during the transition from land to water of cetaceans, and most of these cetacean ERVs were reaching evolutionary dead-ends. 17 ERV lineages are likely to arise from independent retrovirus endogenization events that occurred after the split of mysticetes and odontocetes, indicating that diverse retroviruses infected cetaceans through cross-species transmission from non-cetacean mammals after the transition to aquatic life of cetaceans. Both integration time and synteny analyses support the recent or ongoing activity of multiple retroviral lineages in cetaceans, some of which proliferated into hundreds of copies within the host genomes. Although ERVs only recorded a proportion of past retroviral infections, our findings illuminate the complex evolution of retroviruses during one of the most marked macroevolutionary transitions in vertebrate history.

scholarly journals Ancient and conserved functional interplay between Bcl-2 family proteins in the mitochondrial pathway of apoptosis

2020 ◽  
Vol 6 (40) ◽  
pp. eabc4149 ◽  
Author(s):  
Nikolay Popgeorgiev ◽  
Jaison D Sa ◽  
Lea Jabbour ◽  
Suresh Banjara ◽  
Trang Thi Minh Nguyen ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Ligand Binding ◽  
Cancer Cells ◽  
Mitochondrial Pathway ◽  
Structural Basis ◽  
Mitochondrial Outer Membrane ◽  
Chemotherapy Treatment ◽  
Trichoplax Adhaerens ◽  
Binding Groove

In metazoans, Bcl-2 family proteins are major regulators of mitochondrially mediated apoptosis; however, their evolution remains poorly understood. Here, we describe the molecular characterization of the four members of the Bcl-2 family in the most primitive metazoan, Trichoplax adhaerens. All four trBcl-2 homologs are multimotif Bcl-2 group, with trBcl-2L1 and trBcl-2L2 being highly divergent antiapoptotic Bcl-2 members, whereas trBcl-2L3 and trBcl-2L4 are homologs of proapoptotic Bax and Bak, respectively. trBax expression permeabilizes the mitochondrial outer membrane, while trBak operates as a BH3-only sensitizer repressing antiapoptotic activities of trBcl-2L1 and trBcl-2L2. The crystal structure of a trBcl-2L2:trBak BH3 complex reveals that trBcl-2L2 uses the canonical Bcl-2 ligand binding groove to sequester trBak BH3, indicating that the structural basis for apoptosis control is conserved from T. adhaerens to mammals. Finally, we demonstrate that both trBax and trBak BH3 peptides bind selectively to human Bcl-2 homologs to sensitize cancer cells to chemotherapy treatment.

scholarly journals Modulation of Mitochondrial Outer Membrane Permeabilization and Apoptosis by Ceramide Metabolism

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e48571 ◽  
Author(s):  
António Rego ◽  
Margarida Costa ◽  
Susana Rodrigues Chaves ◽  
Nabil Matmati ◽  
Helena Pereira ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Membrane Permeabilization ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Outer Membrane Permeabilization
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