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TitleGlobal cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST.
Journal, issue, pagesSci Adv, Vol. 11, Issue 4, Page eadu5787, Year 2025
Publish dateJan 24, 2025
AuthorsFelix Kraus / Yuchen He / Sharan Swarup / Katherine A Overmyer / Yizhi Jiang / Johann Brenner / Cristina Capitanio / Anna Bieber / Annie Jen / Nicole M Nightingale / Benton J Anderson / Chan Lee / Joao A Paulo / Ian R Smith / Jürgen M Plitzko / Steven P Gygi / Brenda A Schulman / Florian Wilfling / Joshua J Coon / J Wade Harper /
PubMed AbstractLysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is ...Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multiomic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially in and mutants, where lysosomes accumulate cholesterol. Autophagic and endocytic cargo delivery failures correlated with elevated lysophosphatidylcholine species and multilamellar structures visualized by cryo-electron tomography. Loss of mitochondrial cristae, MICOS complex components, and OXPHOS components rich in iron-sulfur cluster proteins in cells was largely alleviated when iron was provided through the transferrin system. This study reveals how lysosomal dysfunction affects mitochondrial homeostasis and underscores nMOST as a valuable discovery tool for identifying molecular phenotypes across LSDs.
External linksSci Adv / PubMed:39841834 / PubMed Central
MethodsEM (tomography)
Structure data

EMDB-51701: In situ cryo-electron tomogram of a multi-lamellar vesicle in a NPC2-/- HeLa cell. #1
Method: EM (tomography)

EMDB-51702: In situ cryo-electron tomogram of a multi-lamellar vesicle in a NPC2-/- HeLa cell. #2
Method: EM (tomography)

Source
  • Homo sapiens (human)

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