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

作者全名："Yang, Junling; Chen, Xia; Luodan, A.; Gao, Hui; Zhao, Maoru; Ge, Lingling; Li, Minghui; Yang, Cao; Gong, Yu; Gu, Zhanjun; Xu, Haiwei"

作者地址："[Yang, Junling; Chen, Xia; Luodan, A.; Gao, Hui; Ge, Lingling; Li, Minghui; Yang, Cao; Xu, Haiwei] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Southwest Eye Hosp, Chongqing 400038, Peoples R China; [Yang, Junling; Chen, Xia; Luodan, A.; Gao, Hui; Ge, Lingling; Li, Minghui; Yang, Cao; Gong, Yu; Xu, Haiwei] Southwest Hosp, Southwest Eye Hosp, Key Lab Visual Damage & Regenerat & Restorat Chong, Chongqing 400038, Peoples R China; [Zhao, Maoru; Gu, Zhanjun] Chinese Acad Sci, Inst High Energy Phys, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100049, Peoples R China; [Zhao, Maoru; Gu, Zhanjun] Chinese Acad Sci, CAS Ctr Excellence Nanosci, Beijing 100049, Peoples R China; [Zhao, Maoru; Gu, Zhanjun] Chinese Acad Sci, Natl Ctr Nanosci & Technol, Beijing 100049, Peoples R China; [Zhao, Maoru; Gu, Zhanjun] Univ Chinese Acad Sci, Coll Mat Sci & Optoelect Technol, Beijing 100049, Peoples R China; [Gong, Yu] Univ Town Hosp Chongqing Med Univ, Med Sci Res Ctr, Dept Ophthalmol, Chongqing 400038, Peoples R China"

通信作者："Xu, HW (通讯作者)，Third Mil Med Univ, Army Med Univ, Southwest Hosp, Southwest Eye Hosp, Chongqing 400038, Peoples R China.; Gong, Y; Xu, HW (通讯作者)，Southwest Hosp, Southwest Eye Hosp, Key Lab Visual Damage & Regenerat & Restorat Chong, Chongqing 400038, Peoples R China.; Gu, ZJ (通讯作者)，Chinese Acad Sci, Inst High Energy Phys, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100049, Peoples R China.; Gu, ZJ (通讯作者)，Chinese Acad Sci, CAS Ctr Excellence Nanosci, Beijing 100049, Peoples R China.; Gu, ZJ (通讯作者)，Chinese Acad Sci, Natl Ctr Nanosci & Technol, Beijing 100049, Peoples R China."

来源：SMALL

ESI学科分类：MATERIALS SCIENCE

WOS号：WOS:001019709600001

JCR分区：Q1

影响因子：13

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：fullerenols; photoreceptor degeneration; revered mitochondrial dysfunction; therapeutic strategy

摘要："Poor 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."

基金机构："National Key Research and Development Program of China [2021YFA1101203, 2020YFA0710702]; National Natural Science Foundation of China [31930068, 51822207, 51772292]; Science and Technology Innovation Project of Army Medical University [20QNPY025]"

基金资助正文："Acknowledgements J.Y. and X.C. contributed equally to this work. This study was supported by funding from the National Key Research and Development Program of China (Grant Nos. 2021YFA1101203 and 2020YFA0710702), the National Natural Science Foundation of China (Grant Nos. 31930068, 51822207, and 51772292), and the Science and Technology Innovation Project of Army Medical University (Grant Nos. 20QNPY025)."