Blockade of mitochondrial components release by exosome pathway promotes the pathogenesis of Fuchs endothelial corneal dystrophy

TL;DR

This study finds that mitochondrial dysfunction and exosome pathway disruption contribute to the progression of Fuchs endothelial corneal dystrophy.

Contribution

The study identifies mitochondrial proteome changes in aqueous humor and links impaired exosome pathways to FECD pathogenesis.

Findings

44 proteins were upregulated in FECD patient aqueous humor, with mitochondrial components enriched.

Mitochondrial protein TOM20 was reduced in FECD corneal endothelium with damaged mitochondrial ejection.

Exosome inhibition worsened mitochondrial membrane potential and cell death in FECD endothelial cells.

Abstract

Fuchs endothelial corneal dystrophy (FECD) is the leading indication of corneal transplantation worldwide and the focus of pathogenesis has been on the corneal endothelium. Instead of cellular analysis, we aimed to identify the protein changes of aqueous humor (AH) in patients with FECD and investigate in more detail the relationship between AH and corneal endothelium. We collected 13 AH samples of 7 early/middle stage FECD patients and 6 control patients during routine cataract surgery. The proteomes of AH were profiled with the 4D label-free quantitative tandem mass spectrometry. Among 1613 identified proteins, 44 proteins exhibited above two-fold upregulation in the AH of FECD patients than control patients. Gene ontology (GO) analysis showed the enrichment of mitochondrial components, which were further validated by ELISA of mitochondrial proteins SLC25A3, PC, and PARK7. Moreover, immunofluorescence staining and ultrastructural observation were conducted in clinical specimens, mouse corneal endothelium and cultured human corneal endothelial cells (HCECs). The mitochondrial protein TOM20 was reduced in the FECD corneal endothelium, accompanied by damaged mitochondrial ejection. We next isolated extracellular vesicles by ultracentrifugation from HCECs and revealed that the mitochondria copy numbers were significantly increased in UVA-irradiated cells. Inhibition of exosome biogenesis aggravated cell death and mitochondrial membrane potential impairment in FECD endothelial cells. Taken together, our results provided novel insights into the proteome characterization of the AH from FECD patients and offered new perspective to deepen the impaired mitochondrial quality control in the pathogenesis of FECD.

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