Neuropilin-2 Deficiency Promotes Mitochondrial Dysfunction and NAD⁺-Dependent Cellular Senescence in Retinal...

Area of Science:

• Ophthalmology
• Cell Biology
• Mitochondrial Biology

Background:

• Retinal pigment epithelial (RPE) dysfunction drives retinal degenerative diseases and vision loss.
• Mitochondrial impairment and cellular senescence are key pathological drivers in RPE dysfunction.
• Upstream regulators of RPE mitochondrial impairment and senescence are largely unknown.

Purpose of the Study:

• Investigate the role of neuropilin-2 (NRP2) in maintaining RPE homeostasis.
• Explore echinacoside (ECH) as a mitochondrial-targeted therapy for retinal degeneration.

Main Methods:

• Generated RPE-specific Nrp2 conditional knockout mice.
• Assessed retinal morphology and function using fundus imaging, OCT, histology, and ERG.
• Analyzed RPE senescence, mitochondrial function, NAD+ metabolism, and sirtuin activity in vitro and in vivo, evaluating ECH treatment effects.

Main Results:

• NRP2 deletion caused RPE atrophy, photoreceptor loss, and impaired ERG.
• NRP2 deficiency led to mitochondrial dysfunction, elevated ROS, and reduced NAD+/NADH ratios.
• ECH treatment rescued mitochondrial dysfunction and senescence markers, preserving retinal structure and function in vivo.

Conclusions:

• NRP2 is crucial for RPE mitochondrial integrity and NAD+ metabolism.
• Loss of NRP2 disrupts metabolic homeostasis, promoting RPE senescence and retinal degeneration.
• Targeting the NRP2-mitochondria-NAD+ axis with ECH is a potential therapeutic strategy for retinal degenerative diseases.