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

PURPOSE: Retinal pigment epithelial (RPE) dysfunction is a central pathological feature of retinal degenerative diseases, leading to irreversible vision loss. RPE dysfunction is substantially driven by mitochondrial impairment and senescence. However, the upstream regulators of these processes remain largely undefined. This study investigated the role of neuropilin-2 (NRP2) in RPE homeostasis and explored mitochondrial-targeted therapy with echinacoside (ECH) as a potential intervention for retinal degeneration. METHODS: RPE-specific Nrp2 conditional knockout mice were generated using AAV-VMD2-Cre and retinal morphology and function were assessed by fundus imaging, optical coherence tomography, histology, and electroretinogram (ERG). Cellular and metabolic phenotypes were examined in NRP2-deficient ARPE-19 cells and validated in vivo. RPE senescence, mitochondrial function, NAD⁺ metabolism, and sirtuin activity were analyzed, and the effects of ECH treatment were evaluated both in vitro and in vivo. RESULTS: RPE-specific Nrp2 deletion resulted in progressive RPE atrophy, photoreceptor loss, and impaired ERG responses. NRP2 deficiency led to mitochondrial elongation, elevated ROS, membrane depolarization, and reduced NAD⁺/NADH ratios. Decreased NAD⁺ levels were accompanied by downregulation of SIRT1/SIRT3 and increased protein acetylation, promoting RPE senescence. Restoring NAD⁺ levels or ECH treatment rescued mitochondrial dysfunction and reduced senescence markers in vitro. Furthermore, in vivo ECH administration preserved retinal structure and visual function in NRP2-deficient mice. CONCLUSIONS: NRP2 is a critical regulator of mitochondrial integrity and NAD⁺ metabolism in the RPE. Its loss disrupts metabolic homeostasis, promoting RPE senescence and retinal degeneration. Targeting the NRP2-mitochondria-NAD⁺ axis with echinacoside represents a promising therapeutic strategy for preventing retinal degenerative diseases.