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Received: 2022-02-22

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Qiuju WANG


Qingfeng YAN


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Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.2 P.172-184


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

Author(s):  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

Affiliation(s):  College of Life Sciences, Zhejiang University, Hangzhou 310058, China; more

Corresponding email(s):   qfyan@zju.edu.cn, wqcr301@vip.?sina.com

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

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. AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization[J]. Journal of Zhejiang University Science B, 2023, 24(2): 172-184.

@article{title="AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization",
author="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",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization
%A Yue QIU
%A Hongyang WANG
%A Huaye PAN
%A Jing GUAN
%A Lei YAN
%A Mingjie FAN
%A Xuanhao ZHOU
%A Kaiwen WU
%A Zexiao JIA
%A Qianqian ZHUANG
%A Zhaoying LEI
%A Mengyao LI
%A Aifu LIN
%A Yong FU
%A Qiuju WANG
%A Qingfeng YAN
%J Journal of Zhejiang University SCIENCE B
%V 24
%N 2
%P 172-184
%@ 1673-1581
%D 2023
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200081

T1 - AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization
A1 - Yue QIU
A1 - Hongyang WANG
A1 - Huaye PAN
A1 - Jing GUAN
A1 - Lei YAN
A1 - Mingjie FAN
A1 - Hui ZHOU
A1 - Xuanhao ZHOU
A1 - Kaiwen WU
A1 - Zexiao JIA
A1 - Qianqian ZHUANG
A1 - Zhaoying LEI
A1 - Mengyao LI
A1 - Xue DING
A1 - Aifu LIN
A1 - Yong FU
A1 - Dong ZHANG
A1 - Qiuju WANG
A1 - Qingfeng YAN
J0 - Journal of Zhejiang University Science B
VL - 24
IS - 2
SP - 172
EP - 184
%@ 1673-1581
Y1 - 2023
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200081

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 function. ANSD represents up to 15% of individuals with hearing impairments. Through 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 cases. Here, 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 lines. We then analyzed AIF structure, coenzyme-binding affinity, apoptosis, and other aspects. Results revealed that these variants resulted in impaired dimerization, compromising AIF function. The reduction reaction of AIF variants had proceeded slower than that of AIF-WT. The 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 apoptosis. The average percentage of apoptotic cells in the variants was 12.3%‍‒‍17.9%, which was significantly higher than that (6.9%‍‒‍7.4%) in controls. However, nicotinamide adenine dinucleotide (NADH) treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells. Our 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 treatment. Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.




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