NRF2 Deficiency Disrupts Mitochondrial Homeostasis via NDUFS7 in Trabecular Meshwork

TL;DR

This study shows that NRF2 protects the eye's trabecular meshwork by maintaining mitochondrial health, and its deficiency leads to increased eye pressure and potential glaucoma.

Contribution

The study identifies NDUFS7 as a direct NRF2 target critical for mitochondrial function in the trabecular meshwork.

Findings

NRF2 deficiency causes elevated intraocular pressure and mitochondrial dysfunction in the trabecular meshwork.

NDUFS7 restoration rescues mitochondrial impairment in NRF2-deficient cells and mice.

NRF2 overexpression reduces oxidative stress and cytotoxicity in trabecular meshwork cells.

Abstract

The trabecular meshwork (TM) plays a pivotal role in maintaining intraocular pressure (IOP) by regulating aqueous humor outflow. Nuclear factor erythroid 2-related factor 2 (NRF2) was identified as a key transcriptional controller of TM redox balance and mitochondrial function. Transcriptomic profiling of tert-butyl hydroperoxide (tBHP)-induced oxidative injury revealed NRF2 pathway involvement in TM cellular defense. NRF2 knockout (KO) mice exhibited impaired aqueous humor dynamics, elevated IOP, and TM oxidative damage. In vitro, NRF2 knockdown aggravated oxidative stress and mitochondrial dysfunction, whereas NRF2 overexpression mitigated tBHP-induced cytotoxicity. The results of the gene set enrichment analysis (GSEA) indicated enrichment of oxidative phosphorylation pathway in NRF2-deficient cells. Chromatin immunoprecipitation sequencing (ChIP-seq) confirmed NDUFS7 as a direct NRF2 target essential for mitochondrial complex I integrity. Restoration of NDUFS7 expression in NRF2-deficient TM cells or KO mice rescued mitochondrial impairment. Collectively, these findings establish the NRF2/NDUFS7 axis as a central defense mechanism protecting TM from oxidative injury and suggest potential therapeutic strategies for glaucoma-associated ocular hypertension.

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