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Published October 20, 2024 | Version v0.1
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Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST

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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Additional details

Funding

Aligning Science Across Parkinson's
Mechanisms Overwhelming Protein and Organelle Quality Control in Parkinson’s Disease ASAP-000282
Aligning Science Across Parkinson's
Mechanisms Overwhelming Protein and Organelle Quality Control in Parkinson’s Disease ASAP-024268