Bax Assembles into Large Ring-like Structures Remodeling the Mitochondrial Outer Membrane in Apoptosis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2016 Jan 20

PMID 26783364

Citations 139

Authors

Lena Grosse

Christian A Wurm

Christian Bruser

Daniel Neumann

Daniel C Jans

Stefan Jakobs

Affiliations

Soon will be listed here.

Abstract

The Bcl-2 family proteins Bax and Bak are essential for the execution of many apoptotic programs. During apoptosis, Bax translocates to the mitochondria and mediates the permeabilization of the outer membrane, thereby facilitating the release of pro-apoptotic proteins. Yet the mechanistic details of the Bax-induced membrane permeabilization have so far remained elusive. Here, we demonstrate that activated Bax molecules, besides forming large and compact clusters, also assemble, potentially with other proteins including Bak, into ring-like structures in the mitochondrial outer membrane. STED nanoscopy indicates that the area enclosed by a Bax ring is devoid of mitochondrial outer membrane proteins such as Tom20, Tom22, and Sam50. This strongly supports the view that the Bax rings surround an opening required for mitochondrial outer membrane permeabilization (MOMP). Even though these Bax assemblies may be necessary for MOMP, we demonstrate that at least in Drp1 knockdown cells, these assemblies are not sufficient for full cytochrome c release. Together, our super-resolution data provide direct evidence in support of large Bax-delineated pores in the mitochondrial outer membrane as being crucial for Bax-mediated MOMP in cells.

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References

Grosse L, Wurm C, Bruser C, Neumann D, Jans D, Jakobs S . Bax assembles into large ring-like structures remodeling the mitochondrial outer membrane in apoptosis. EMBO J. 2016; 35(4):402-13. PMC: 4755111. DOI: 10.15252/embj.201592789. View

Kroemer G, Galluzzi L, Brenner C . Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007; 87(1):99-163. DOI: 10.1152/physrev.00013.2006. View

Eskes R, Desagher S, Antonsson B, Martinou J . Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol. 2000; 20(3):929-35. PMC: 85210. DOI: 10.1128/MCB.20.3.929-935.2000. View

Martinez-Caballero S, Dejean L, Kinnally M, Oh K, Mannella C, Kinnally K . Assembly of the mitochondrial apoptosis-induced channel, MAC. J Biol Chem. 2009; 284(18):12235-45. PMC: 2673292. DOI: 10.1074/jbc.M806610200. View

Gross A, Jockel J, Wei M, Korsmeyer S . Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J. 1998; 17(14):3878-85. PMC: 1170723. DOI: 10.1093/emboj/17.14.3878. View

Kuwana T, Mackey M, Perkins G, Ellisman M, Latterich M, Schneiter R . Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell. 2002; 111(3):331-42. DOI: 10.1016/s0092-8674(02)01036-x. View

Zhou L, Chang D . Dynamics and structure of the Bax-Bak complex responsible for releasing mitochondrial proteins during apoptosis. J Cell Sci. 2008; 121(Pt 13):2186-96. DOI: 10.1242/jcs.024703. View

Nechushtan A, Smith C, Lamensdorf I, Yoon S, Youle R . Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J Cell Biol. 2001; 153(6):1265-76. PMC: 2192024. DOI: 10.1083/jcb.153.6.1265. View

Renault T, Manon S . Bax: Addressed to kill. Biochimie. 2011; 93(9):1379-91. DOI: 10.1016/j.biochi.2011.05.013. View

10.

Hell S . Microscopy and its focal switch. Nat Methods. 2009; 6(1):24-32. DOI: 10.1038/nmeth.1291. View

11.

AlKhaja A, Jans D, Nikolov M, Vukotic M, Lytovchenko O, Ludewig F . MINOS1 is a conserved component of mitofilin complexes and required for mitochondrial function and cristae organization. Mol Biol Cell. 2011; 23(2):247-57. PMC: 3258170. DOI: 10.1091/mbc.E11-09-0774. View

12.

Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko G, Rudka T . OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 2006; 126(1):177-89. DOI: 10.1016/j.cell.2006.06.025. View

13.

Yang R, Zhao G, Liang S, Zhang Y, Sun L, Chen H . Mitofilin regulates cytochrome c release during apoptosis by controlling mitochondrial cristae remodeling. Biochem Biophys Res Commun. 2012; 428(1):93-8. DOI: 10.1016/j.bbrc.2012.10.012. View

14.

von der Malsburg K, Muller J, Bohnert M, Oeljeklaus S, Kwiatkowska P, Becker T . Dual role of mitofilin in mitochondrial membrane organization and protein biogenesis. Dev Cell. 2011; 21(4):694-707. DOI: 10.1016/j.devcel.2011.08.026. View

15.

Hsu Y, Wolter K, Youle R . Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. Proc Natl Acad Sci U S A. 1997; 94(8):3668-72. PMC: 20498. DOI: 10.1073/pnas.94.8.3668. View

16.

Kluck R, Bossy-Wetzel E, Green D, Newmeyer D . The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science. 1997; 275(5303):1132-6. DOI: 10.1126/science.275.5303.1132. View

17.

Jans D, Wurm C, Riedel D, Wenzel D, Stagge F, Deckers M . STED super-resolution microscopy reveals an array of MINOS clusters along human mitochondria. Proc Natl Acad Sci U S A. 2013; 110(22):8936-41. PMC: 3670330. DOI: 10.1073/pnas.1301820110. View

18.

Edlich F, Banerjee S, Suzuki M, Cleland M, Arnoult D, Wang C . Bcl-x(L) retrotranslocates Bax from the mitochondria into the cytosol. Cell. 2011; 145(1):104-16. PMC: 3070914. DOI: 10.1016/j.cell.2011.02.034. View

19.

Harner M, Korner C, Walther D, Mokranjac D, Kaesmacher J, Welsch U . The mitochondrial contact site complex, a determinant of mitochondrial architecture. EMBO J. 2011; 30(21):4356-70. PMC: 3230385. DOI: 10.1038/emboj.2011.379. View

20.

Schellenberg B, Wang P, Keeble J, Rodriguez-Enriquez R, Walker S, Owens T . Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming. Mol Cell. 2013; 49(5):959-71. PMC: 3594749. DOI: 10.1016/j.molcel.2012.12.022. View