title: Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders.
abstract: Mitochondrial diseases are systemic, prevalent and often fatal; yet treatments remain scarce. Identifying molecular intervention points that can be therapeutically targeted remains a major challenge, which we confronted via a screening assay we developed. Using yeast models of mitochondrial ATP synthase disorders, we screened a drug repurposing library, and applied genomic and biochemical techniques to identify pathways of interest. Here we demonstrate that modulating the sorting of nuclear-encoded proteins into mitochondria, mediated by the TIM23 complex, proves therapeutic in both yeast and patient-derived cells exhibiting ATP synthase deficiency. Targeting TIM23-dependent protein sorting improves an array of phenotypes associated with ATP synthase disorders, including biogenesis and activity of the oxidative phosphorylation machinery. Our study establishes mitochondrial protein sorting as an intervention point for ATP synthase disorders, and because of the central role of this pathway in mitochondrial biogenesis, it holds broad value for the treatment of mitochondrial diseases.
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Raeka S
authors.initials: RS
authors.lastname: Aiyar
authors.affiliation: Institut für Biochemie und Molekularbiologie, ZBMZ, Universität Freiburg, 79104 Freiburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Bohnert
authors.affiliation: 1] Université Bordeaux, IBGC, UMR 5095, F-33000 Bordeaux, France [2] CNRS, IBGC, UMR 5095, F-33000 Bordeaux, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Duvezin-Caubet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1078; Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest F-29200, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Voisset
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Julien
authors.initials: J
authors.lastname: Gagneur
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Emilie S
authors.initials: ES
authors.lastname: Fritsch
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1078; Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest F-29200, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Couplan
authors.affiliation: 1] Institut für Biochemie und Molekularbiologie, ZBMZ, Universität Freiburg, 79104 Freiburg, Germany [2] BIOSS Centre for Biological Signalling Studies, Universität Freiburg, 79104 Freiburg, Germany.
authors.forename: Karina
authors.initials: K
authors.lastname: von der Malsburg
authors.affiliation: European Molecular Biology Laboratory (EMBL), Electron Microscopy Core Facility, 69117 Heidelberg, Germany.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Funaya
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1078; Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest F-29200, France.
authors.forename: Flavie
authors.initials: F
authors.lastname: Soubigou
authors.affiliation: 1] Université Bordeaux, IBGC, UMR 5095, F-33000 Bordeaux, France [2] CNRS, IBGC, UMR 5095, F-33000 Bordeaux, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Courtin
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, California 94304, USA.
authors.forename: Sundari
authors.initials: S
authors.lastname: Suresh
authors.affiliation: Department of Genetics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Roza
authors.initials: R
authors.lastname: Kucharczyk
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1078; Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest F-29200, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Evrard
authors.affiliation: European Molecular Biology Laboratory (EMBL), Electron Microscopy Core Facility, 69117 Heidelberg, Germany.
authors.forename: Claude
authors.initials: C
authors.lastname: Antony
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, California 94304, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: St Onge
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR1078; Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest F-29200, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Blondel
authors.affiliation: 1] Université Bordeaux, IBGC, UMR 5095, F-33000 Bordeaux, France [2] CNRS, IBGC, UMR 5095, F-33000 Bordeaux, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: di Rago
authors.affiliation: 1] Institut für Biochemie und Molekularbiologie, ZBMZ, Universität Freiburg, 79104 Freiburg, Germany [2] BIOSS Centre for Biological Signalling Studies, Universität Freiburg, 79104 Freiburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: van der Laan
authors.affiliation: 1] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany [2] Stanford Genome Technology Center, Stanford University, Palo Alto, California 94304, USA [3] Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Steinmetz
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D062313:Databases, Pharmaceutical; D058492:Drug Repositioning; D005786:Gene Expression Regulation; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D025261:Mitochondrial Proton-Translocating ATPases / Q000172:deficiency / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013871:Thiones / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009687:Nuclear Proteins; D011725:Pyridines; D029701:Saccharomyces cerevisiae Proteins; C083081:TIM23 protein, S cerevisiae; C438387:TIMM23 protein, human; D013871:Thiones; C008704:pyrithione; D025261:Mitochondrial Proton-Translocating ATPases