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Lysosomal storage disease proteo/lipidomic profiling using nMOST links ferritinophagy with mitochondrial iron deficiencies in cells lacking NPC2.
Kraus, Felix; He, Yuchen; Swarup, Sharan; Overmyer, Katherine A; Jiang, Yizhi; Brenner, Johann; Capitanio, Cristina; Bieber, Anna; Jen, Annie; Nightingale, Nicole M; Anderson, Benton J; Lee, Chan; Paulo, Joao A; Smith, Ian R; Plitzko, Jürgen M; Schulman, Brenda A; Wilfling, Florian; Coon, Joshua J; Wade Harper, J.
Afiliación
  • Kraus F; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • He Y; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
  • Swarup S; equal contribution.
  • Overmyer KA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Jiang Y; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Brenner J; equal contribution.
  • Capitanio C; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Bieber A; equal contribution.
  • Jen A; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Nightingale NM; Morgridge Institute for Research, Madison, WI 53715, USA.
  • Anderson BJ; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Lee C; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Paulo JA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
  • Smith IR; Mechanisms of Cellular Quality Control, Max Planck Institute of Biophysics, Frankfurt, Germany.
  • Plitzko JM; CryoEM Technology, Max Planck Institute of Biochemistry, Munich, Germany.
  • Schulman BA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
  • Wilfling F; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • Coon JJ; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
  • Wade Harper J; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
bioRxiv ; 2024 Mar 27.
Article en En | MEDLINE | ID: mdl-38585873
ABSTRACT
Lysosomal storage diseases (LSDs) comprised ~50 monogenic diseases characterized by the accumulation of cellular material in lysosomes and associated defects in lysosomal function, but systematic molecular phenotyping is lacking. Here, we develop a nanoflow-based multi-omic single-shot technology (nMOST) workflow allowing simultaneously quantify HeLa cell proteomes and lipidomes from more than two dozen LSD mutants, revealing diverse molecular phenotypes. Defects in delivery of ferritin and its autophagic receptor NCOA4 to lysosomes (ferritinophagy) were pronounced in NPC2-/- cells, which correlated with increased lyso-phosphatidylcholine species and multi-lamellar membrane structures visualized by cryo-electron-tomography. Ferritinophagy defects correlated with loss of mitochondrial cristae, MICOS-complex components, and electron transport chain complexes rich in iron-sulfur cluster proteins. Strikingly, mitochondrial defects were alleviated when iron was provided through the transferrin system. This resource reveals how defects in lysosomal function can impact mitochondrial homeostasis in trans and highlights nMOST as a discovery tool for illuminating molecular phenotypes across LSDs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos