title: MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria.
abstract: Mitochondria exert critical functions in cellular lipid metabolism and promote the synthesis of major constituents of cellular membranes, such as phosphatidylethanolamine (PE) and phosphatidylcholine. Here, we demonstrate that the phosphatidylserine decarboxylase Psd1, located in the inner mitochondrial membrane, promotes mitochondrial PE synthesis via two pathways. First, Ups2-Mdm35 complexes (SLMO2-TRIAP1 in humans) serve as phosphatidylserine (PS)-specific lipid transfer proteins in the mitochondrial intermembrane space, allowing formation of PE by Psd1 in the inner membrane. Second, Psd1 decarboxylates PS in the outer membrane in trans, independently of PS transfer by Ups2-Mdm35. This latter pathway requires close apposition between both mitochondrial membranes and the mitochondrial contact site and cristae organizing system (MICOS). In MICOS-deficient cells, limiting PS transfer by Ups2-Mdm35 and reducing mitochondrial PE accumulation preserves mitochondrial respiration and cristae formation. These results link mitochondrial PE metabolism to MICOS, combining functions in protein and lipid homeostasis to preserve mitochondrial structure and function.
authors.affiliation: Institute of Genetics, University of Cologne, 50931 Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Mari J
authors.initials: MJ
authors.lastname: Aaltonen
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Friedman
authors.affiliation: Institute of Genetics, University of Cologne, 50931 Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Osman
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, Centre National de la Recherche Scientifique UMR5095, Université Bordeaux Segalen, Bordeaux 33077, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Salin
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, Centre National de la Recherche Scientifique UMR5095, Université Bordeaux Segalen, Bordeaux 33077, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: di Rago
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616.
authors.forename: Jodi
authors.initials: J
authors.lastname: Nunnari
authors.affiliation: Institute of Genetics, University of Cologne, 50931 Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany t.tatsuta@uni-koeln.de thomas.langer@uni-koeln.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langer
authors.affiliation: Institute of Genetics, University of Cologne, 50931 Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany t.tatsuta@uni-koeln.de thomas.langer@uni-koeln.de.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tatsuta
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D017353:Gene Deletion; D008563:Membrane Lipids / Q000096:biosynthesis*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism / Q000648:ultrastructure; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: C552370:Mdm35 protein, S cerevisiae; D008563:Membrane Lipids; D024101:Mitochondrial Proteins; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines; D010743:Phospholipids; D021122:Protein Subunits; D029701:Saccharomyces cerevisiae Proteins; C542159:Ups2 protein, S cerevisiae; C483858:phosphatidylethanolamine