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

Abstract

Retinitis pigmentosa (RP) is a hereditary neurodegenerative disease characterized by the degeneration of photoreceptors caused by mutations in various genes. Increasing evidence suggests that mitochondrial biogenesis plays a critical role in many neurodegenerative diseases. This study investigated the role of mitochondrial biogenesis in rd1 mice, a widely recognized model of RP. Male C57BL/6 mice and age-matched rd1 mice were used for in vivo experiments, while H₂O₂ was employed on 661w cells to establish an in vitro model. Our findings revealed that mitochondrial biogenesis and the regulatory PGC-1α/NRF-1/TFAM pathway were significantly downregulated in rd1 mice. Treatment with ZLN005, a PGC-1α agonist, markedly improved visual function in rd1 mice and alleviated thinning of the retinal outer nuclear layer. Additionally, ZLN005 enhanced mitochondrial biogenesis and restored mitochondrial function in photoreceptors. Further analysis in vitro confirmed that ZLN005 rescued photoreceptor degeneration by promoting mitochondrial biogenesis through the PGC-1α/NRF-1/TFAM pathway. In summary, our results highlight the critical role of mitochondrial biogenesis and the PGC-1α/NRF-1/TFAM pathway in the progression of RP. This offers a potential strategy to delay photoreceptor degeneration in RP by maintaining mitochondrial function and could be combined with existing therapies for improving treatment outcomes through synergistic pathways.

Keywords: Animal study; Mitochondrial biogenesis; Mitochondrial dysfunction; Retinitis pigmentosa; ZLN005.