NAD+ modulates mitochondrial vulnerability in MERTK-associated models of retinitis pigmentosa

Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease leading to blindness. RP is characterized by progressive loss of photoreceptors and retinal pigment epithelium (RPE), leading to retinal degeneration. The mechanisms that initiate RP and drive retinal vulnerability are poorly understood, and new strategies for preventing and treating RP are urgently needed. Although mitochondrial dysfunction initiates many neurodegenerative diseases, the contribution of mitochondrial dysfunction to RP is unclear. Single-cell RNA sequencing, transmission electron microscopy, and enzyme-linked immunosorbent assays revealed that photoreceptor and RPE cells have abnormal mitochondria in rats with RP. Nicotinamide adenine dinucleotide (NAD+) metabolism decreased in rats with RP, increasing the vulnerability to disease-related insults. Similar experimental results were observed in a Mer tyrosine kinase receptor (MERTK)-associated RP primary human RPE cell model. Electroretinography, immunofluorescence, and fundus photography revealed that oral administration of the NAD+ precursor nicotinamide mononucleotide (NMN) protected rats with RP from retinal degeneration. Single-cell RNA sequencing, siRNA targeting, and Adeno-associated virus applications demonstrated that NMN elicits therapeutic effects via the glyceraldehyde-phosphate dehydrogenase-mitochondria pathway. These results indicate that mitochondrial abnormalities may be drivers of RP, and NMN elicits therapeutic effects on RP.