Purpose

To explore the role of mitochondrial function in the inflammatory and adipogenic responses of orbital fibroblasts (OFs) in Graves’ orbitopathy (GO).

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Methods

Orbital connective tissue was obtained from GO patients and control subjects. Primary OFs were cultured and stimulated with IL-1β or TNF-α, with or without oligomycin (a mitochondrial ATP synthase inhibitor) or resveratrol (a mitochondrial enhancer). Inflammatory cytokine expression (IL-6, IL-8, PGE2, COX-2) was evaluated using qPCR, ELISA, and Western blotting. Phosphorylation of MEK1/2, NF-κB, and p38 MAPK was analyzed. Mitochondrial activity was assessed by ATP levels, mtDNA copy number, mGOT activity, and MitoTracker staining. Adipogenesis was induced for 10 days, and lipid accumulation was assessed via Oil Red O staining and triglyceride assays.
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Results

GO orbital tissues exhibited significantly increased ATP levels, mtDNA copy number, and mGOT activity compared with controls, indicating a metabolically activated state.IL-1β robustly induced inflammatory cytokine expression in GO orbital fibroblasts, which was further enhanced by oligomycin and suppressed by resveratrol. Mitochondrial inhibition amplified IL-1β–induced p38 MAPK phosphorylation, whereas resveratrol broadly suppressed MEK1/2, NF-κB, and p38 activation. During adipogenic differentiation, mitochondrial content and ATP production increased progressively. Oligomycin enhanced, while resveratrol markedly attenuated, lipid accumulation and triglyceride synthesis in both GO and non-GO fibroblasts.

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Conclusion

Mitochondrial function critically regulates both inflammatory signaling and adipogenic differentiation in orbital fibroblasts from Graves’ orbitopathy. Mitochondrial dysfunction amplifies pro-inflammatory responses and promotes adipogenesis, whereas mitochondrial enhancement exerts suppressive effects. These findings identify mitochondria as a central immuno-metabolic modulator in GO and support mitochondrial regulation as a potential therapeutic strategy.

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Additional Authors

First name	Last name	Base Hospital / Institution
Sun Young	Jang	Soonchunhyang University Bucheon Hospital
Ja Young	Oh	Chung-Ang University Gwangmyeong Hospital
Gyeongmin	Lee	Hallym university kangnam sacred heart hospital
Yeon Jeong	Choi	Soonchunhyang University Bucheon Hospital
Jin Sook	Yoon	Severance Hospital, The Institute of Vision Research, Yonsei University College of Medicine
Nam Ju	Kim	Seoul National University Bundang Hospital
Yeong A	Choi	Ewha Womans University Seoul Hospital

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