title: Bax assembles into large ring-like structures remodeling the mitochondrial outer membrane in apoptosis.
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.
authors.affiliation: Department of Neurology, University Medical Center of Göttingen, Göttingen, Germany Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Große
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Wurm
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Brüser
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neumann
authors.affiliation: Department of Neurology, University Medical Center of Göttingen, Göttingen, Germany Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany djans@gwdg.de sjakobs@gwdg.de.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Jans
authors.affiliation: Department of Neurology, University Medical Center of Göttingen, Göttingen, Germany Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany djans@gwdg.de sjakobs@gwdg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jakobs
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000201:enzymology* / Q000502:physiology; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000502:physiology; D010539:Permeability; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism*; D055503:Protein Multimerization; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; D052899:Pore Forming Cytotoxic Proteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c
keywords: Bcl‐2; MICOS; cell death; membrane curvature; superresolution microscopy