title: Bid-cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome C release.
abstract: Release of cytochrome c from the mitochondrial intermembrane space is critical to apoptosis induced by a variety of death stimuli. Bid is a BH3-only prodeath Bcl-2 family protein that can potently activate this efflux. In the current study, we investigated the mitochondrial localization of Bid and its interactions with mitochondrial phospholipids, focusing on their relationships with Bid-induced cytochrome c release. We found that Bid binding to the mitochondria required only three of its eight helical structures (alpha4-alpha6), but not the BH3 domain, and the binding could not be inhibited by the antideath molecule Bcl-x(L). Membrane fractionations indicated that tBid bound to mitochondrial outer membranes at both contact and noncontact sites. Bid could interact with specific cardiolipin species on intact mitochondria as identified by mass spectrometry. Like the binding to the mitochondria, this interaction could not be blocked by the mutation in the BH3 domain or by Bcl-x(L.) However, a cardiolipin-specific dye, 10-N-nonyl acridine orange, could preferentially suppress Bid binding to the mitochondrial contact site and inhibit Bid-induced mitochondrial cristae reorganization and cytochrome c release. These findings thus suggest that interactions of Bid with mitochondrial cardiolipin at the contact site can contribute significantly to its functions.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Tae-Hyoung
authors.initials: TH
authors.lastname: Kim
authors.forename: Yongge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
authors.forename: Jin Na
authors.initials: JN
authors.lastname: Shin
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Seo
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Hannah
authors.initials: H
authors.lastname: Rabinowich
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Amoscato
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yin
mesh_terms: D000609:Aminoacridines / Q000494:pharmacology; D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein; D002308:Cardiolipins / Q000032:analysis / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: D000609:Aminoacridines; D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494812:Bcl2l1 protein, mouse; C494815:Bid protein, mouse; D002308:Cardiolipins; D002352:Carrier Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C041691:10-N-nonylacridinium orange; D045304:Cytochromes c