Heteroplasmic and homoplasmic m.616T > C in mitochondria tRNA(Phe) promote isolated chronic kidney disease and hyperuricemia

作者全名:"Xu, Chengxian; Tong, Lingxiao; Rao, Jia; Ye, Qing; Chen, Yuxia; Zhang, Yingying; Xu, Jie; Mao, Xiaoting; Meng, Feilong; Shen, Huijun; Lu, Zhihong; Cang, Xiaohui; Fu, Haidong; Wang, Shugang; Gu, Weiyue; Lai, En-Yin; Guan, Min-Xin; Jiang, Pingping; Mao, Jianhua"

作者地址:"[Xu, Chengxian; Tong, Lingxiao; Zhang, Yingying; Xu, Jie; Meng, Feilong; Shen, Huijun; Lu, Zhihong; Cang, Xiaohui; Fu, Haidong; Guan, Min-Xin; Jiang, Pingping; Mao, Jianhua] Zhejiang Univ, Childrens Hosp, Dept Nephrol, Sch Med, Hangzhou 310052, Peoples R China; [Xu, Chengxian; Tong, Lingxiao; Zhang, Yingying; Xu, Jie; Meng, Feilong; Shen, Huijun; Lu, Zhihong; Cang, Xiaohui; Fu, Haidong; Guan, Min-Xin; Jiang, Pingping; Mao, Jianhua] Natl Clin Res Ctr Child Hlth, Hangzhou 310058, Peoples R China; [Rao, Jia] Fudan Univ, Natl Pediat Med Ctr China, Dept Nephrol, Childrens Hosp, Shanghai, Peoples R China; [Ye, Qing] Zhejiang Univ, Zhejiang Key Lab Neonatal Dis, Childrens Hosp, Sch Med, Hangzhou, Peoples R China; [Chen, Yuxia] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Rehabil Med,Chongqing Key Lab Pediat, Minist Educ,Key Lab Child Dev & Disorders,Childre, Chongqing, Peoples R China; [Mao, Xiaoting; Cang, Xiaohui; Guan, Min-Xin; Jiang, Pingping] Zhejiang Univ, Inst Genet, Sch Med, Hangzhou 310058, Peoples R China; [Mao, Xiaoting; Cang, Xiaohui; Guan, Min-Xin; Jiang, Pingping] Zhejiang Univ, Dept Human Genet, Sch Med, Hangzhou, Peoples R China; [Wang, Shugang; Gu, Weiyue] Chigene Beijing Translat Med Res Ctr Co Ltd, Beijing, Peoples R China; [Lai, En-Yin] Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou, Peoples R China"

通信作者:"Mao, JH (通讯作者),Zhejiang Univ, Childrens Hosp, Dept Nephrol, Sch Med, Hangzhou 310052, Peoples R China.; Jiang, PP (通讯作者),Natl Clin Res Ctr Child Hlth, Hangzhou 310058, Peoples R China.; Guan, MX (通讯作者),Zhejiang Univ, Inst Genet, Sch Med, Hangzhou 310058, Peoples R China.; Jiang, PP (通讯作者),Zhejiang Univ, Childrens Hosp, Sch Med, Hangzhou 310058, Peoples R China."

来源:JCI INSIGHT

ESI学科分类:CLINICAL MEDICINE

WOS号:WOS:000810022500001

JCR分区:Q1

影响因子:8

年份:2022

卷号:7

期号:11

开始页: 

结束页: 

文献类型:Article

关键词: 

摘要:"Inherited kidney diseases are the fifth most common cause of end-stage renal disease (ESRD). Mitochondrial dysfunction plays a vital role in the progression of inherited kidney diseases, while mitochondrial-transfer RNA (mt-tRNA) variants and their pathogenic contributions to kidney disease remain largely unclear. In this study, we identified the pathogenic mt-tRNA(Phe) 616T>C mutation in 3 families and documented that m.616T>C showed a high pathogenic threshold, with both heteroplasmy and homoplasmy leading to isolated chronic kidney disease and hyperuricemia without hematuria, proteinuria, or renal cyst formation. Moreover, 1 proband with homoplamic m.616T>C presented ESRD as a child. No symptoms of nervous system evolvement were observed in these families. Lymphoblast cells bearing m.616T>C exhibited swollen mitochondria, underwent active mitophagy, and showed respiratory deficiency, leading to reduced mitochondrial ATP production, diminished membrane potential, and overproduction of mitochondrial ROS. Pathogenic m.616T>C abolished a highly conserved base pair (A31-U39) in the anticodon stem-loop which altered the structure of mt-tRNA(Phe), as confirmed by a decreased melting temperature and slower electrophoretic mobility of the mutant tRNA. Furthermore, the unstable structure of mt-tRNA(Phe) contributed to a shortage of steady-state mt-tRNA(Phe) and enhanced aminoacylation efficiency, which resulted in impaired mitochondrial RNA translation and a significant decrease in mtDNA-encoded polypeptides. Collectively, these findings provide potentially new insights into the pathogenesis underlying inherited kidney disease caused by mitochondrial variants."

基金机构:"National Natural Science Foundation of China [U20A20351, 81870314]; Zhejiang Provincial Program for the Culti-vation of High-level Innovative Health Talents; Major projects joint-ly constructed by Zhejiang province [WKJ-ZJ-1908]; National Health Commission of China; Key Research and Development Plan of Zhejiang Province [2021C03079]"

基金资助正文:We are grateful to all patients and family members for their participation. This work was supported by grant U20A20351 from the National Natural Science Foundation of China (to JM) ; grant 81870314 from the National Natural Science Foundation of China (to PJ) ; the Zhejiang Provincial Program for the Culti-vation of High-level Innovative Health Talents (to PJ) ; grant WKJ-ZJ-1908 from the Major projects joint-ly constructed by Zhejiang province and the National Health Commission of China (to JM) ; and grant 2021C03079 from the Key Research and Development Plan of Zhejiang Province (to JM) .