title: Distribution and apoptotic function of outer membrane proteins depend on mitochondrial fusion.
abstract: Cells deficient in mitochondrial fusion have been shown to have defects linked to the exchange of inner membrane and matrix components. Because outer-mitochondrial membrane (OMM) constituents insert directly from the cytoplasm, a role for fusion in their intermitochondrial transfer was unanticipated. Here, we show that fibroblasts lacking the GTPases responsible for OMM fusion, mitofusins 1 and 2 (MFN1 and MFN2), display more heterogeneous distribution of OMM proteins. Proteins with different modes of OMM association display varying degrees of heterogeneity in Mfn1/2(-/-) cells and different kinetics of transfer during fusion in fusion-competent cells. Proapoptotic Bak exhibits marked heterogeneity, which is normalized upon expression of MFN2. Bak is critical for Bid-induced OMM permeabilization and cytochrome c release, and Mfn1/2(-/-) cells show dysregulation of Bid-dependent apoptotic signaling. Bid sensitivity of Bak-deficient mitochondria is regained upon fusion with Bak-containing mitochondria. Thus, OMM protein distribution depends on mitochondrial fusion and is a locus of apoptotic dysfunction in conditions of fusion deficiency.
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: David
authors.initials: D
authors.lastname: Weaver
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Verónica
authors.initials: V
authors.lastname: Eisner
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Xingguo
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Physiology, Semmelweis University, Budapest 1085, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Várnai
authors.affiliation: Department of Physiology, Semmelweis University, Budapest 1085, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Hunyady
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Atan
authors.initials: A
authors.lastname: Gross
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: gyorgy.hajnoczky@jefferson.edu.
authors.forename: György
authors.initials: G
authors.lastname: Hajnóczky
mesh_terms: D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D063154:Mitochondrial Dynamics; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D050996:Voltage-Dependent Anion Channel 2 / Q000235:genetics; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494815:Bid protein, mouse; D024101:Mitochondrial Proteins; C494766:Vdac2 protein, mouse; D050996:Voltage-Dependent Anion Channel 2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse