Bax assembly into rings and arcs in apoptotic mitochondria is linked to membrane pores

Salvador‐Gallego, Raquel; Mund, Markus; Cosentino, Katia; Schneider, Jale; Unsay, Joseph D.; Schraermeyer, Ulrich; Engelhardt, Johann; Ries, Jonas; García‐Sáez, Ana J.

doi:10.15252/embj.201593384

Cited by 259 publications

(275 citation statements)

References 51 publications

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“…Regulatory interactions between Bax and other Bcl-2 proteins can only be observed in the presence of the OMM or liposomes (17,18). Recent studies suggest that Bax is inserted in mitochondrial membranes as a monomer that oligomerizes once inserted (19)(20)(21). These studies also have shown that Bcl-x L inhibits Bax by dissociating Bax oligomers.…”

mentioning

confidence: 99%

Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes

Andreu-Férnández

Sancho

Genovés

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The Bcl-2 (B-cell lymphoma 2) protein Bax (Bcl-2 associated X, apoptosis regulator) can commit cells to apoptosis via outer mitochondrial membrane permeabilization. Bax activity is controlled in healthy cells by prosurvival Bcl-2 proteins. C-terminal Bax transmembrane domain interactions were implicated recently in Bax pore formation. Here, we show that the isolated transmembrane domains of Bax, Bcl-x L (B-cell lymphoma-extra large), and Bcl-2 can mediate interactions between Bax and prosurvival proteins inside the membrane in the absence of apoptotic stimuli. Bcl-2 protein transmembrane domains specifically homooligomerize and heterooligomerize in bacterial and mitochondrial membranes. Their interactions participate in the regulation of Bcl-2 proteins, thus modulating apoptotic activity. Our results suggest that interactions between the transmembrane domains of Bax and antiapoptotic Bcl-2 proteins represent a previously unappreciated level of apoptosis regulation.

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mentioning

confidence: 99%

Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes

Andreu-Férnández

Sancho

Genovés

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The timing 'before' and 'after' refers to the time at which changes are observed relative to MOMP. Adapted with permission from (Crimi and Degli Esposti 2011) More recently, the presence of large ring-like structures formed by Bax oligomers on MOM was detected in apoptotic cells (Große et al 2016;Salvador-Gallego et al 2016) (Fig. 5b).…”

Section: The Structure Of the Apoptotic Porementioning

confidence: 85%

“…Involvement of proteins other than Bax and Bak may assist in pore formation. Intriguingly, arc structures are also able to cause membrane permeabilization (Salvador-Gallego et al 2016). The existence of different Bax organization in the membrane such as ring-like, lines and arcs structures indicate that the mechanistic details of Bax/Bak-mediated permeabilization are not entirely understood.…”

Section: The Structure Of the Apoptotic Porementioning

confidence: 99%

“…The existence of different Bax organization in the membrane such as ring-like, lines and arcs structures indicate that the mechanistic details of Bax/Bak-mediated permeabilization are not entirely understood. However, these structures may represent various stages in Bax pore formation (Salvador-Gallego et al 2016). Fig.…”

Section: The Structure Of the Apoptotic Porementioning

confidence: 99%

“…This study revealed the presence of linear and arc clusters that do not perforate the membrane, which lead to complete membrane pores, corresponding to full rings or partially arcs (SalvadorGallego et al 2016). Reproduced with permission from Salvador-Gallego et al (2016 and It has also been proposed that membrane-curvature stress induces Bax-mediated pore formation and subsequent MOMP (Gillies et al 2015). In the toroidal pore, Bax/Bak localize and oligomerize at this site leading to pore formation whereby more Bax monomers enter and provide more curvature stress (Gillies et al 2015).…”

Section: The Structure Of the Apoptotic Porementioning

confidence: 99%

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Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

et al. 2017

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Apoptosis is important in regulating cell death turnover and is mediated by the intrinsic and death receptor-based extrinsic pathways which converge at the mitochondrial outer membrane (MOM) leading to mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of apoptotic proteins that further activate the downstream pathway of apoptosis. Thus, tight regulation of MOMP is crucial in controlling apoptosis, and a lack of control may lead to tissue and organ malformation and the development of cancers. Despite a growing number of studies focusing on the structure and activity of the proteins involved in mediating MOMP, such as the Bcl-2 family proteins, the mechanism of MOMP is not well understood. In particular, the crucial role of the various structural properties and changes in lipid components of the MOM in mediating the recruitment and activation of different Bcl-2 proteins remains poorly understood. Furthermore, the factors that control the changes in mitochondrial membrane integrity from the initiation to the final disruption of MOM have yet to be clearly defined. In this review, we provide an overview of studies that focus on the mitochondrial membrane with a biophysical analysis of the interactions of the Bcl-2 proteins with the mitochondrial membrane.

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New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

et al. 2019

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Cytochrome c (Cc) is a protein that functions as an electron carrier in the mitochondrial respiratory chain. However, Cc has moonlighting roles outside mitochondria driving the transition of apoptotic cells from life to death. When living cells are damaged, Cc escapes its natural mitochondrial environment and, once in the cytosol, it binds other proteins to form a complex named the apoptosome—a platform that triggers caspase activation and further leads to controlled cell dismantlement. Early released Cc also binds to inositol 1,4,5‐triphosphate receptors on the ER membrane, which stimulates further massive Cc release from mitochondria. Besides the well‐characterized binding proteins contributing to the proapoptotic functions of Cc, many novel protein targets have been recently described. Among them, histone chaperones were identified as key partners of Cc following DNA breaks, indicating that Cc might modulate chromatin dynamics through competitive binding to histone chaperones. In this article, we review the ample set of recently discovered antiapoptotic proteins—involved in DNA damage, transcription, and energetic metabolism—reported to interact with Cc in the cytoplasm and even the nucleus upon DNA breaks.

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Bax assembly into rings and arcs in apoptotic mitochondria is linked to membrane pores

Cited by 259 publications

References 51 publications

Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes

Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes

Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

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