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Inhibition of STING Protects the Neuroretina in an Ndufs4 Knockout Mouse Model of Mitochondrial Complex 1 Deficiency
Jong-Jer Lee1, Yu-Ting Hsiao2, Hsiu-Mei Huang2
1Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Ophthalmology, Kaohsiung Municipal Feng Shan Hospital-Under the management of Chang Gung Medical Foundation, Kaohsiung, Taiwan; Center for Mitochondrial Research and Medicine, College of Medicine Chang Gung University, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
Purpose:
Ndufs4 encodes a key subunit of mitochondrial complex I, and its mutation causes NADH dehydrogenase deficiency associated with Leigh syndrome and Leber hereditary optic neuropathy. In Ndufs4 knockout (KO) mice, vision loss occurs alongside an "inflammatory wave" that disrupts neuroretinal function. In this study, we explore a novel inflammation-driven pathogenic mechanism and whether treatments targeting inflammatory pathways can mitigate neuroretina degeneration.
Methods:
Transcriptomic analysis of neuroretinal tissue from Ndufs4-KO mice identified immune-response activation as the most enriched pathway, with a twofold upregulation of stimulator of interferon genes (STING). Based on these findings, Ndufs4-KO mice received intraperitoneal injections of the STING inhibitors C-176 or SN-011 three times weekly from postnatal day 29 to 42; controls received vehicle only. Inflammatory cytokines were measured using ELISA, while retinal structure and function were evaluated through immunofluorescence and electroretinography (ERG).
Results:
Immunofluorescence showed infiltration of Iba1-positive microglia into inner retinal layers of Ndufs4-KO mice, which was reduced by nearly 50% following C-176 and SN-011 treatment. ELISA confirmed decreased levels of the inflammatory markers CCL5 and ICAM-1. Untreated Ndufs4 retinas exhibited thinning of the inner retinal layers to about 70% of normal, whereas treated mice retained ∼85-90% of control thickness. ERG recordings demonstrated significantly improved retinal responses after STING inhibition.
Conclusions:
STING inhibition preserves neuroretina structure and function, highlighting its role in Ndufs4 pathology. This is the first study to show improved ERG responses following treatment in Ndufs4-KO mice, supporting STING as a promising therapeutic target for mitochondrial NADH dehydrogenase deficiency disorders.
