Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders

Raeka S. Aiyar, Maria Bohnert, Stéphane Duvezin-Caubet, Cécile Voisset, Julien Gagneur, Emilie S. Fritsch, Elodie Couplan, Karina von der Malsburg, Charlotta Funaya, Flavie Soubigou, Florence Courtin, Sundari Suresh, Roza Kucharczyk, Justine Evrard, Claude Antony, Robert P. St.Onge, Marc Blondel, Jean-Paul di Rago, Martin van der Laan () and Lars M. Steinmetz ()
Additional contact information
Raeka S. Aiyar: European Molecular Biology Laboratory (EMBL), Genome Biology Unit
Maria Bohnert: Institut für Biochemie und Molekularbiologie, ZBMZ, Universität Freiburg
Stéphane Duvezin-Caubet: Université Bordeaux, IBGC, UMR 5095
Cécile Voisset: 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
Julien Gagneur: European Molecular Biology Laboratory (EMBL), Genome Biology Unit
Emilie S. Fritsch: European Molecular Biology Laboratory (EMBL), Genome Biology Unit
Elodie Couplan: 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
Karina von der Malsburg: Institut für Biochemie und Molekularbiologie, ZBMZ, Universität Freiburg
Charlotta Funaya: European Molecular Biology Laboratory (EMBL), Electron Microscopy Core Facility
Flavie Soubigou: 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
Florence Courtin: Université Bordeaux, IBGC, UMR 5095
Sundari Suresh: Stanford Genome Technology Center, Stanford University
Roza Kucharczyk: Institute of Biochemistry and Biophysics, Polish Academy of Sciences
Justine Evrard: 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
Claude Antony: European Molecular Biology Laboratory (EMBL), Electron Microscopy Core Facility
Robert P. St.Onge: Stanford Genome Technology Center, Stanford University
Marc Blondel: 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
Jean-Paul di Rago: Université Bordeaux, IBGC, UMR 5095
Martin van der Laan: Institut für Biochemie und Molekularbiologie, ZBMZ, Universität Freiburg
Lars M. Steinmetz: European Molecular Biology Laboratory (EMBL), Genome Biology Unit

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6585

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