title: Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins.
abstract: Mitochondrial injury, characterized by outer membrane permeabilization and consequent release of apoptogenic factors, is a key to apoptosis of mammalian cells. Bax and Bak, two multidomain Bcl-2 family proteins, provide a requisite gateway to mitochondrial injury. However it is unclear how Bax and Bak cooperate to provoke mitochondrial injury and whether their roles are redundant. Here, we have identified a unique role of Bak in mitochondrial fragmentation, a seemingly morphological event that contributes to mitochondrial injury during apoptosis. We show that mitochondrial fragmentation is attenuated in Bak-deficient mouse embryonic fibroblasts, baby mouse kidney cells, and, importantly, also in primary neurons isolated from brain cortex of Bak-deficient mice. In sharp contrast, Bax deficiency does not prevent mitochondrial fragmentation during apoptosis. Bcl-2 and Bcl-XL inhibit mitochondrial fragmentation, and their inhibitory effects depend on the presence of Bak. Reconstitution of Bak into Bax/Bak double-knockout cells restores mitochondrial fragmentation, whereas reconstitution of Bax is much less effective. Bak interacts with Mfn1 and Mfn2, two mitochondrial fusion proteins. During apoptosis, Bak dissociates from Mfn2 and enhances the association with Mfn1. Mutation of Bak in the BH3 domain prevents its dissociation from Mfn2 and diminishes its mitochondrial fragmentation activity. This study has uncovered a previously unrecognized function of Bak in the regulation of mitochondrial morphological dynamics during apoptosis. By this function, Bak may collaborate with Bax to permeabilize the outer membrane of mitochondria, unleashing the apoptotic cascade.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia and Veterans Affairs Medical Center, Augusta, GA 30912, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Brooks
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wei
authors.forename: Leping
authors.initials: L
authors.lastname: Feng
authors.forename: Guie
authors.initials: G
authors.lastname: Dong
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Tao
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Zi-Jian
authors.initials: ZJ
authors.lastname: Xie
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010539:Permeability; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse