Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST
Creators
- 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.
- Gygi, Steven P.
- Schulman, Brenda A.
- Wilfling, Florian
- Coon, Joshua J.
- Harper, J. Wade
Description
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 multi-omic 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 NPC1-/- and NPC2-/- mutants, where lysosomes accumulate cholesterol. Autophagic and endocytic cargo delivery failures correlated with elevated lyso-phosphatidylcholine species and multi-lamellar structures visualized by cryo-electron tomography. Loss of mitochondrial cristae, MICOS-complex components, and OXPHOS components rich in iron-sulfur cluster proteins in NPC2-/- 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.
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