title: A mitochondria-anchored isoform of the actin-nucleating spire protein regulates mitochondrial division.
abstract: Mitochondrial division, essential for survival in mammals, is enhanced by an inter-organellar process involving ER tubules encircling and constricting mitochondria. The force for constriction is thought to involve actin polymerization by the ER-anchored isoform of the formin protein inverted formin 2 (INF2). Unknown is the mechanism triggering INF2-mediated actin polymerization at ER-mitochondria intersections. We show that a novel isoform of the formin-binding, actin-nucleating protein Spire, Spire1C, localizes to mitochondria and directly links mitochondria to the actin cytoskeleton and the ER. Spire1C binds INF2 and promotes actin assembly on mitochondrial surfaces. Disrupting either Spire1C actin- or formin-binding activities reduces mitochondrial constriction and division. We propose Spire1C cooperates with INF2 to regulate actin assembly at ER-mitochondrial contacts. Simulations support this model's feasibility and demonstrate polymerizing actin filaments can induce mitochondrial constriction. Thus, Spire1C is optimally positioned to serve as a molecular hub that links mitochondria to actin and the ER for regulation of mitochondrial division.
authors: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, United States.
authors: Uri
authors: http://orcid.org/0000-0002-9802-1955
authors: U
authors: Manor
authors: Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.
authors: Sadie
authors: S
authors: Bartholomew
authors: Department of Physiology and Pharmacology, Tel Aviv University, Tel Aviv, Israel.
authors: Gonen
authors: G
authors: Golani
authors: Unit on Structural and Chemical Biology of Membrane Proteins, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, United States.
authors: Eric
authors: E
authors: Christenson
authors: Department of Physiology and Pharmacology, Tel Aviv University, Tel Aviv, Israel.
authors: Michael
authors: M
authors: Kozlov
authors: Department of Biochemistry, Geisel School of Medicine, Hanover, United States.
authors: Henry
authors: H
authors: Higgs
authors: Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.
authors: James
authors: J
authors: Spudich
authors: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, United States.
authors: Jennifer
authors: J
authors: Lippincott-Schwartz
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003599:Cytoskeleton / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000080865:Formins; D005786:Gene Expression Regulation; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000502:physiology*; D063154:Mitochondrial Dynamics; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D000080865:Formins; C546959:INF2 protein, human; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000592292:SPIRE1 protein, human
keywords: actin; cell biology; cytoskeleton; endoplasmic reticulum; human; membranes; mitochondria; mouse; organelles