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Integrated proteomic profiling of human and murine tear fluid reveals ER-mitochondrial lipid crosstalk and organelle stress signaling in dry eye disease

ABSTRACT: This project presents comprehensive proteomic profiling of human and murine tear fluid samples in the context of dry eye disease (DED). Human tear proteomics revealed significant activation of the PERK-ATF4 integrated stress response axis, coordinated reprogramming of mitochondrial bioenergetics (TCA cycle enzymes including IDH3A, ECHS1), and dysregulation of sterol/lipid transport pathways. Murine tear proteomics further demonstrated disruptions in endoplasmic reticulum-mitochondrial lipid exchange, including altered phospholipid transport, mitochondrial-associated endoplasmic reticulum membrane (MAM) integrity, and lipid biosynthesis pathways. Protein-protein interaction network analyses identified FABP5 as a key molecular hub coordinating intracellular lipid trafficking and metabolic adaptation. Collectively, these multi-omics datasets establish that DED is characterized by ER-mitochondrial lipid crosstalk disruption and organelle stress signaling, providing mechanistic insights and therapeutic entry points for restoring ocular surface lipid homeostasis. Raw mass spectrometry data for both human and mouse samples have been deposited in the iProX database.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Yangbao Miao

PROVIDER: PXD076652 | iProX | Sat Apr 04 00:00:00 BST 2026

REPOSITORIES: iProX

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Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late onset ALS. Although ALS results from MN’s death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a FUSR521H or a FUSP525L mutation and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette as described previously in our lab. Mutant and control iPSC differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Subsequent lipidomics studies demonstrated defects in myelin lipids, with a reduction of phospholipids in mutant OPCs. Among them, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most two abundant phospholipid in mammalian cells and regulate the mitochondria-associated ER membrane (MAM) integrity. Interestingly, FUSR521H mutant OPCs displayed a decrease in the PC/PE ratio, known to be associated with maintaining membrane (mitochondria) integrity. Proximity ligation assay further indicated that MAM was diminished in mutant OPCs. Moreover, mutant OPCs displayed stronger activation of unfolded protein response markers, a hallmark of increased susceptibility to endoplasmic reticulum (ER) stress, when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca2+ signaling from ER Ca2+ stores. Taken together, these results demonstrate that FUS mutant OPCs display defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and suppressed physiological Ca2+ signaling events.

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Integrated proteomic profiling of human and murine tear fluid reveals ER-mitochondrial lipid crosstalk and organelle stress signaling in dry eye disease

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