Xiaoli Zhang, Shun Yao, Lujia Zhang, Beisi Zhang, Mingzhu Yang, Qingge Guo, Jin Xu, Zhongfeng Wang, Bo Lei, Xiuxiu Jin
{"title":"与 ARL3 基因突变相关的视杆细胞色素营养不良症中的线粒体功能障碍","authors":"Xiaoli Zhang, Shun Yao, Lujia Zhang, Beisi Zhang, Mingzhu Yang, Qingge Guo, Jin Xu, Zhongfeng Wang, Bo Lei, Xiuxiu Jin","doi":"10.1096/fba.2023-00138","DOIUrl":null,"url":null,"abstract":"<p>Mitochondria are vital for retinal cell function and survival, and there is growing evidence linking mitochondrial dysfunction to retinal degenerations. Although <i>ARL3</i> mutations have been linked to multiple forms of retinal degeneration, the relationship between ARL3 and mitochondria remains unexplored. Herein, we investigated the effects of <i>ARL3</i><sup><i>T31A</i></sup>, <i>ARL3</i><sup><i>C118F</i></sup>, and <i>ARL3</i><sup><i>T31A/C118F</i></sup> mutations on mitochondrial function in fibroblasts obtained from patients with ARL3-related rod-cone dystrophy. Our findings revealed that these mutations led to a decrease in mitochondrial respiration, an increase in the accumulation mitochondrial reactive oxygen species (ROS), and induction of apoptosis in fibroblasts. Additionally, we conducted a comparative analysis of the effects of ARL3<sup>T31A</sup>, ARL3<sup>C118F</sup>, and ARL3<sup>T31A/C118F</sup> proteins on mitochondria in ARPE-19 cells. Results showed that ARL3<sup>T31A</sup> and ARL3<sup>T31A/C118F</sup> not only affected mitochondrial function but also induced apoptosis in ARPE-19 cells. Conversely, ARL3<sup>C118F</sup> primarily influenced cell apoptosis with minimal effects on mitochondrial function in ARPE-19 cells. Transcriptome analysis further suggested the involvement of respiratory electron transport, response to ROS, and apoptotic signaling pathways in ARL3<sup>T31A/C118F</sup> cells. Our study demonstrated that <i>ARL3</i>-related mutations play a significant role in the diversity of mitochondrial function, providing novel insights into the functional analysis of <i>ARL3</i>-related mutations.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00138","citationCount":"0","resultStr":"{\"title\":\"Mitochondrial functional impairment in ARL3-mutation related rod-cone dystrophy\",\"authors\":\"Xiaoli Zhang, Shun Yao, Lujia Zhang, Beisi Zhang, Mingzhu Yang, Qingge Guo, Jin Xu, Zhongfeng Wang, Bo Lei, Xiuxiu Jin\",\"doi\":\"10.1096/fba.2023-00138\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Mitochondria are vital for retinal cell function and survival, and there is growing evidence linking mitochondrial dysfunction to retinal degenerations. Although <i>ARL3</i> mutations have been linked to multiple forms of retinal degeneration, the relationship between ARL3 and mitochondria remains unexplored. Herein, we investigated the effects of <i>ARL3</i><sup><i>T31A</i></sup>, <i>ARL3</i><sup><i>C118F</i></sup>, and <i>ARL3</i><sup><i>T31A/C118F</i></sup> mutations on mitochondrial function in fibroblasts obtained from patients with ARL3-related rod-cone dystrophy. Our findings revealed that these mutations led to a decrease in mitochondrial respiration, an increase in the accumulation mitochondrial reactive oxygen species (ROS), and induction of apoptosis in fibroblasts. Additionally, we conducted a comparative analysis of the effects of ARL3<sup>T31A</sup>, ARL3<sup>C118F</sup>, and ARL3<sup>T31A/C118F</sup> proteins on mitochondria in ARPE-19 cells. Results showed that ARL3<sup>T31A</sup> and ARL3<sup>T31A/C118F</sup> not only affected mitochondrial function but also induced apoptosis in ARPE-19 cells. Conversely, ARL3<sup>C118F</sup> primarily influenced cell apoptosis with minimal effects on mitochondrial function in ARPE-19 cells. Transcriptome analysis further suggested the involvement of respiratory electron transport, response to ROS, and apoptotic signaling pathways in ARL3<sup>T31A/C118F</sup> cells. Our study demonstrated that <i>ARL3</i>-related mutations play a significant role in the diversity of mitochondrial function, providing novel insights into the functional analysis of <i>ARL3</i>-related mutations.</p>\",\"PeriodicalId\":12093,\"journal\":{\"name\":\"FASEB bioAdvances\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-09-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00138\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"FASEB bioAdvances\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1096/fba.2023-00138\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"FASEB bioAdvances","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1096/fba.2023-00138","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Mitochondrial functional impairment in ARL3-mutation related rod-cone dystrophy
Mitochondria are vital for retinal cell function and survival, and there is growing evidence linking mitochondrial dysfunction to retinal degenerations. Although ARL3 mutations have been linked to multiple forms of retinal degeneration, the relationship between ARL3 and mitochondria remains unexplored. Herein, we investigated the effects of ARL3T31A, ARL3C118F, and ARL3T31A/C118F mutations on mitochondrial function in fibroblasts obtained from patients with ARL3-related rod-cone dystrophy. Our findings revealed that these mutations led to a decrease in mitochondrial respiration, an increase in the accumulation mitochondrial reactive oxygen species (ROS), and induction of apoptosis in fibroblasts. Additionally, we conducted a comparative analysis of the effects of ARL3T31A, ARL3C118F, and ARL3T31A/C118F proteins on mitochondria in ARPE-19 cells. Results showed that ARL3T31A and ARL3T31A/C118F not only affected mitochondrial function but also induced apoptosis in ARPE-19 cells. Conversely, ARL3C118F primarily influenced cell apoptosis with minimal effects on mitochondrial function in ARPE-19 cells. Transcriptome analysis further suggested the involvement of respiratory electron transport, response to ROS, and apoptotic signaling pathways in ARL3T31A/C118F cells. Our study demonstrated that ARL3-related mutations play a significant role in the diversity of mitochondrial function, providing novel insights into the functional analysis of ARL3-related mutations.