title: Coincident Phosphatidic Acid Interaction Restrains Drp1 in Mitochondrial Division.
abstract: Mitochondria divide to control their size, distribution, turnover, and function. Dynamin-related protein 1 (Drp1) is a critical mechanochemical GTPase that drives constriction during mitochondrial division. It is generally believed that mitochondrial division is regulated during recruitment of Drp1 to mitochondria and its oligomerization into a division apparatus. Here, we report an unforeseen mechanism that regulates mitochondrial division by coincident interactions of Drp1 with the head group and acyl chains of phospholipids. Drp1 recognizes the head group of phosphatidic acid (PA) and two saturated acyl chains of another phospholipid by penetrating into the hydrophobic core of the membrane. The dual phospholipid interactions restrain Drp1 via inhibition of oligomerization-stimulated GTP hydrolysis that promotes membrane constriction. Moreover, a PA-producing phospholipase, MitoPLD, binds Drp1, creating a PA-rich microenvironment in the vicinity of a division apparatus. Thus, PA controls the activation of Drp1 after the formation of the division apparatus.
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Kie
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Biology, Reed College, Portland, OR 97202, USA.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Cerveny
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Takamichi L
authors.initials: TL
authors.lastname: Suzuki
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Macdonald
authors.affiliation: Department of Pharmacological Sciences and Center for Developmental Genetics, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Frohman
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ramachandran
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: miijima@jhmi.edu.
authors.forename: Miho
authors.initials: M
authors.lastname: Iijima
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: hsesaki@jhmi.edu.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
mesh_terms: D000818:Animals; D001665:Binding Sites; D034281:Dynamins / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000235:genetics*; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D010712:Phosphatidic Acids / Q000378:metabolism*; D010739:Phospholipase D / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D024101:Mitochondrial Proteins; D010712:Phosphatidic Acids; D006160:Guanosine Triphosphate; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D010739:Phospholipase D; C558126:mitoPLD protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins