Junling Yang, Xia Chen, Luodan A, Hui Gao, Maoru Zhao, Lingling Ge, Minghui Li, Cao Yang, Yu Gong, Zhanjun Gu, Haiwei Xu

Alleviation of Photoreceptor Degeneration Based on Fullerenols in rd1 Mice by Reversing Mitochondrial Dysfunction via Modulation of Mitochondrial DNA Transcription and Leakage

  • Biomaterials
  • Biotechnology
  • General Materials Science
  • General Chemistry
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AbstractPoor therapeutic outcomes of antioxidants in ophthalmologic clinical applications, including glutathione during photoreceptor degeneration in retinitis pigmentosa (RP), are caused by limited anti‐oxidative capacity. In this study, fullerenols are synthesized and proven to be highly efficient in vitro radical scavengers. Fullerenol‐based intravitreal injections significantly improve the flash electroretinogram and light/dark transition tests performed for 28 days on rd1 mice, reduce the thinning of retinal outer nuclear layers, and preserve the Rhodopsin, Gnat‐1, and Arrestin expressions of photoreceptors. RNA‐sequencing, RT‐qPCR, and Western blotting validate that mitochondrial DNA (mt‐DNA)‐encoded genes of the electron transport chain (ETC), such as mt‐Nd4l, mt‐Co1, mt‐Cytb, and mt‐Atp6, are drastically downregulated in the retinas of rd1 mice, whereas nuclear DNA (n‐DNA)‐encoded genes, such as Ndufa1 and Atp5g3, are abnormally upregulated. Fullerenols thoroughly reverse the abnormal mt‐DNA and n‐DNA expression patterns of the ETC and restore mitochondrial function in degenerating photoreceptors. Additionally, fullerenols simultaneously repress Flap endonuclease 1 (FEN1)‐mediated mt‐DNA cleavage and mt‐DNA leakage via voltage‐dependent anion channel (VDAC) pores by downregulating the transcription of Fen1 and Vdac1, thereby inactivating the downstream pro‐inflammatory cGAS‐STING pathway. These findings demonstrate that fullerenols can effectively alleviate photoreceptor degeneration in rd1 mice and serve as a viable treatment for RP.

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