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

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

  • Neuropharmacology. 2025 May 15:269:110361. doi: 10.1016/j.neuropharm.2025.110361.
Chengyu Hu 1,  Chengda Ren 2,  Yan Wu 1,  Ruoyi Lin 1,  Tianyi Shen 1,  Tingting Li 3,  Donghui Yu 4,  Lei Jiang 1,  Zhongqi Wan 1,  Yunhong Luo 1,  Tu Su 1,  Jing Yu 5,  Yaoyan Qiu 6
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
  • 2 Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 3 Department of Ophthalmology, East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 4 Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Department of Ophthalmology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China; Department of Ophthalmology, The Third People's Hospital of Bengbu, Bengbu, China. Electronic address: 1300221@tongji.edu.cn.
  • 6 Department of Ophthalmology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China. Electronic address: 522639875@qq.com.
PMID: 39952351 DOI: 10.1016/j.neuropharm.2025.110361
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.

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