NRF2 Deficiency Disrupts Mitochondrial Homeostasis via NDUFS7 in Trabecular Meshwork

Area of Science:

• Ocular Biology
• Molecular Biology
• Biochemistry

Background:

• The trabecular meshwork (TM) is vital for regulating intraocular pressure (IOP) by controlling aqueous humor outflow.
• Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of cellular redox balance and mitochondrial function in the TM.

Purpose of the Study:

• To investigate the role of NRF2 in protecting the TM from oxidative stress and its impact on IOP regulation.
• To identify specific molecular targets of NRF2 involved in TM mitochondrial function.

Main Methods:

• Transcriptomic profiling of TM cells exposed to tert-butyl hydroperoxide (tBHP) to identify NRF2 pathway involvement.
• Utilizing NRF2 knockout (KO) mice and in vitro NRF2 knockdown/overexpression models.
• Gene set enrichment analysis (GSEA) and chromatin immunoprecipitation sequencing (ChIP-seq) to identify NRF2 targets.

Main Results:

• NRF2 deficiency in mice led to impaired aqueous humor dynamics, elevated IOP, and TM oxidative damage.
• In vitro, NRF2 knockdown worsened oxidative stress and mitochondrial dysfunction, while NRF2 overexpression provided protection.
• NDUFS7 was identified as a direct NRF2 target essential for mitochondrial complex I integrity, and its restoration rescued mitochondrial function.

Conclusions:

• The NRF2/NDUFS7 axis is a critical defense mechanism against oxidative injury in the TM.
• Dysregulation of this pathway contributes to elevated IOP and TM damage.
• Targeting the NRF2/NDUFS7 pathway offers potential therapeutic strategies for glaucoma and ocular hypertension.