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bioRxiv · 10.1101/2025.09.21.677625

Inferring systemic metabolic and oxidative stress susceptibility in normal-tension glaucoma through targeted skin fibroblast analysis

von Spreckelsen, A.·Dittlau, K. S.·Saruhanian, S.·Vohra, R.·Saruhanian, A.·Aldana, B. I.·Freude, K. K.·Kolko, M.
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Abstract

AimEnhance the understanding of intrinsic metabolic and oxidative stress vulnerability in normal-tension glaucoma (NTG) pathophysiology by targeted profiling of skin fibroblasts from NTG and control donors. BackgroundNTG is a primary open-angle glaucoma subtype characterised by glaucomatous neurodegeneration without elevated intraocular pressure. Increasing evidence links systemic metabolic and oxidative stress vulnerability to NTG pathophysiology, making non-ocular, somatic cells promising surrogate systems for assessing neurodegenerative predisposing mechanisms. MethodsSkin fibroblast cultures were obtained from four female NTG and four age- and gender-matched control donors. Targeted metabolic profiling of mitochondrial function, glycolytic capacity, and glucose and amino acid metabolism was performed using the Seahorse assay, gas chromatography-mass spectrometry, and high-performance liquid chromatography. Oxidative stress resilience to hydrogen peroxide was assessed employing the lactate dehydrogenase release assay. ResultsPure skin fibroblast cultures were obtained for all included donors. NTG and control fibroblast exhibited similar mitochondrial and glycolytic function. No group difference was demonstrated in relative glucose metabolism and absolute amino acid profile. Control and NTG fibroblasts exhibited similar susceptibility to oxidative stress. ConclusionNTG skin fibroblasts exhibit similar mitochondrial and glycolytic function, glucose metabolisation, amino acid profile, and oxidative stress resiliency compared to controls. Future studies should focus on mapping cell- and tissue-specific differences through combined genetic and transcriptomic profiling to guide and stratify the functional assessment of different endotypes within the NTG disease spectrum. Cell-specific dysregulation and the need for individual mechanistic grouping diminish the applicability of skin fibroblasts as a model system for exploiting NTG pathophysiology.

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von Spreckelsen, A., Dittlau, K. S., Saruhanian, S., Vohra, R., Saruhanian, A., Aldana, B. I., Freude, K. K., Kolko, M.. 2025-09-24. Inferring systemic metabolic and oxidative stress susceptibility in normal-tension glaucoma through targeted skin fibroblast analysis. https://doi.org/10.1101/2025.09.21.677625

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