ZLN005, a PGC-1α agonist, delays photoreceptor degeneration by enhancing mitochondrial biogenesis in a murine model of retinitis pigmentosa

Retinitis pigmentosa (RP) is a hereditary neurodegenerative disorder marked by the progressive loss of photoreceptors, driven by mutations in a variety of genes. Emerging evidence suggests that impaired mitochondrial biogenesis contributes to the pathogenesis of several neurodegenerative diseases. In this study, we explored the role of mitochondrial biogenesis in rd1 mice, a widely used model of RP. Male C57BL/6 and age-matched rd1 mice were used for in vivo experiments, while hydrogen peroxide (H₂O₂) was applied to 661w cells to model oxidative stress-induced degeneration in vitro.

Our findings demonstrated a significant downregulation of mitochondrial biogenesis and the associated PGC-1α/NRF-1/TFAM signaling pathway in rd1 mice. Treatment with ZLN005, a pharmacological activator of PGC-1α, significantly improved visual function, mitigated retinal outer nuclear layer thinning, and enhanced mitochondrial biogenesis and function in photoreceptors. Consistent in vitro results showed that ZLN005 protected against photoreceptor degeneration by upregulating the PGC-1α/NRF-1/TFAM axis.

Conclusion: These results underscore the pivotal role of mitochondrial biogenesis in the progression of RP and suggest that targeting the PGC-1α/NRF-1/TFAM pathway may be a promising therapeutic strategy. Enhancing mitochondrial function with agents like ZLN005 may offer synergistic benefits when combined with existing RP treatments.