Endothelin-1 Mediated Decrease in Mitochondrial Gene Expression and Bioenergetics Contribute to Neurodegeneration of...

Area of Science:

• Ophthalmology
• Neuroscience
• Molecular Biology

Background:

• Endothelin-1 (ET-1) is elevated in primary open angle glaucoma (POAG) patients.
• ET-1 is implicated in retinal ganglion cell (RGC) apoptosis and optic nerve axon degeneration, but mechanisms are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms by which ET-1 induces RGC neurodegeneration.
• To identify ET-1-mediated changes in gene expression and mitochondrial function in RGCs.

Main Methods:

• RNA-sequencing (RNA-seq) to analyze ET-1-mediated gene expression changes in primary RGCs.
• Western blotting and Seahorse ATP rate assay to assess mitochondrial protein expression and function.
• In vivo studies involving intravitreal ET-1 injection in rats and induced ocular hypertension (IOP) in Brown Norway rats.

Main Results:

• RNA-seq identified mitochondrial dysfunction, particularly oxidative phosphorylation, as a key pathway affected by ET-1.
• ET-1 significantly decreased protein levels of mitochondrial genes (COX17, ATP5H) in RGCs and in vivo.
• ET-1 treatment reduced mitochondrial ATP production rate, and elevated IOP showed a trend towards decreased ATP5H expression.

Conclusions:

• ET-1 disrupts mitochondrial electron transport chain components, compromising cellular bioenergetics.
• This mitochondrial dysfunction presents a novel mechanism for ET-1-induced RGC neurodegeneration in glaucoma.
• Targeting ET-1's impact on mitochondrial function may offer therapeutic strategies for glaucoma.