AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization

作     者：YUE QIU HONGYANG WANG HUAYE PAN JING GUAN LEI YAN MINGJIE FAN HUI ZHOU XUANHAO ZHOU KAIWEN WU ZEXIAO JIA QIANQIAN ZHUANG ZHAOYING LEI MENGYAO LI XUE DING AIFU LIN YONG FU DONG ZHANG QIUJU WANG QINGFENG YAN Yue QIU;Hongyang WANG;Huaye PAN;Jing GUAN;Lei YAN;Mingjie FAN;Hui ZHOU;Xuanhao ZHOU;Kaiwen WU;Zexiao JIA;Qianqian ZHUANG;Zhaoying LEI;Mengyao LI;Xue DING;Aifu LIN;Yong FU;Dong ZHANG;Qiuju WANG;Qingfeng YAN

作者机构：College of Life SciencesZhejiang UniversityHangzhou 310058China Senior Department of OtolaryngologyHead and Neck SurgeryChinese PLA Institute of OtolaryngologyChinese PLA General HospitalBeijing 100853China Department of Pediatricsthe First Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310003China The Children's Hospital of Zhejiang University School of MedicineHangzhou 310052China Key Laboratory for Cell and Gene Engineering of Zhejiang ProvinceHangzhou 310058China 

出 版 物：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 (浙江大学学报（英文版）B辑（生物医学与生物技术）)

年 卷 期：2023年第24卷第2期

页      面：172-184页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100213[医学-耳鼻咽喉科学] 0836[工学-生物工程] 10[医学] 

基　　金：the National Natural Science Foundation of China(Nos.32070584,81830028,31771398,82222016,and 8207040100) the Zhejiang Provincial Natural Science Foundation of China(No.LZ19C060001) the Fundamental Research Funds for the Central Universities(No.2019QNA6001) 

主　　题：Auditory neuropathy spectrum disorder Apoptosis-inducing factor(AIF)mitochondria-associated 1(AIFM1)variants Dimerization Caspase-independent apoptosis Nicotinamide adenine dinucleotide(NADH)treatment 

摘      要：Auditory neuropathy spectrum disorder(ANSD)represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function,but with the preservation of outer hair cell *** represents up to 15%of individuals with hearing *** mutation screening,bioinformatic analysis and expression studies,we have previously identified several apoptosis-inducing factor(AIF)mitochondria-associated 1(AIFM1)variants in ANSD families and in some other sporadic ***,to elucidate the pathogenic mechanisms underlying each AIFM1 variant,we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)system and constructed AIF-wild type(WT)and AIF-mutant(mut)(p.T260A,p.R422W,and p.R451Q)stable transfection cell *** then analyzed AIF structure,coenzyme-binding affinity,apoptosis,and other *** revealed that these variants resulted in impaired dimerization,compromising AIF *** reduction reaction of AIF variants had proceeded slower than that of *** average levels of AIF dimerization in AIF variant cells were only 34.5%-49.7%of that of AIF-WT cells,resulting in caspase-independent *** average percentage of apoptotic cells in the variants was 12.3%-17.9%,which was significantly higher than that(6.9%-7.4%)in ***,nicotinamide adenine dinucleotide(NADH)treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant *** findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD,and introduce NADH as a potential drug for ANSD *** results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.