Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency
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Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) ISSN 1673-1581 (Print); ISSN 1862-1783 (Online) www.jzus.zju.edu.cn; www.springerlink.com E-mail: [email protected]
Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency*# Ting CHEN§1,2, Fan TONG§1, Xiao-yu WU2, Ling ZHU1,2, Qiu-zi YI2, Jing ZHENG1, Ru-lai YANG1, Zheng-yan ZHAO1, Xiao-hui CANG1,2, Qiang SHU†‡1, Ping-ping JIANG†‡1,2 1
Division of Medical Genetics and Genomics, The Children’s Hospital, Zhejiang University School of Medicine / National Clinical Research Center for Child Health, Hangzhou 310052, China
2
Institute of Genetics and Department of Human Genetics, Zhejiang University School of Medicine, Hangzhou 310058, China †
E-mail: [email protected]; [email protected]
Received June 22, 2020; Revision accepted Aug. 16, 2020; Crosschecked Oct. 13, 2020
Abstract: The pathogenesis of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is highly heterogeneous and still unclear. Additional novel variants have been recently detected in the population. The molecular and cellular effects of these previously unreported variants are still poorly understood and require further characterization. To address this problem, we have evaluated the various functions and biochemical consequences of six novel missense variants that lead to mild VLCAD deficiency. Marked deficiencies in fatty acid oxidation (FAO) and other mitochondrial defects were observed in cells carrying one of these six variants (c.541C>T, c.863T>G, c.895A>G, c.1238T>C, c.1276G>A, and c.1505T>A), including reductions in mitochondrial respiratory-chain function and adenosine triphosphate (ATP) production, and increased levels of mitochondrial reactive oxygen species (ROS). Intriguingly, higher apoptosis levels were found in cells carrying the mutant VLCAD under glucose-limited stress. Moreover, the stability of the mutant homodimer was disturbed, and major conformational changes in each mutant VLCAD structure were predicted by molecular dynamics (MD) simulation. The data presented here may provide valuable information for improving management of diagnosis and treatment of VLCAD deficiency and for a better understanding of the general molecular bases of disease variability. Key words: Mitochondrial dysfunction; Very-long-chain acyl-CoA dehydrogenase (VLCAD); β-Oxidation; Molecular dynamics (MD) simulation https://doi.org/10.1631/jzus.B2000339 CLC number: R725.8
1 Introduction
‡
Corresponding authors The two authors contributed equally to this work * Project supported by the National Natural Science Foundation of China (No. 81741090), the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents, and the National Key R&D Program of China (Nos. 2017YFC1001703 and 2018YFC1002700) # Electronic supplementary materials: The online version of this article (https://doi.org/10.1631/jzus.B2000339) contains supplementary materials, which are available to authorized users ORCID: Ting CHEN, https://
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