REV-ERBα regulates photoreceptor metabolism and visual function and protects against inherited retinal degeneration

Abstract The retina is a metabolically demanding tissue essential for visual function. Disruptions in retinal metabolic pathways are linked to degenerative eye diseases like retinitis pigmentosa (RP). In this study, we found that REV-ERBα ( Nr1d1 ), a nuclear receptor central to mitochondrial biogenesis, is critical for retinal metabolism, visual function, and protects against retinal degeneration. Expression of REV-ERBα is present throughout retinal cells, with high levels in photoreceptors. Both systemic genetic deletion and rod photoreceptor specific deletion of REV-ERBα in mice resulted in dampened visual function with reduced amplitude of a- and b-waves in the electroretinogram. REV-ERBα-deficient retinas and photoreceptor cells exhibited impaired mitochondrial function with decreased oxygen consumption and altered expression of metabolic genes. Importantly, activation of REV-ERBα with a synthetic agonist SR9009 substantially delayed photoreceptor loss in an rd10 genetic mouse model of RP, with slower retinal thinning, reduced levels of photoreceptor apoptosis, and partially preserved visual function. Together, our findings position REV-ERBα as a critical regulator of retinal and photoreceptor metabolism and function, and a promising therapeutic target for addressing retinal degeneration. Modulating REV-ERBα activity may offer a novel strategy for protecting retinal neurons and mitigating vision loss in eye diseases like RP.