Full Text:   <1910>

Summary:  <1642>

Suppl. Mater.: 

CLC number: R725.8

On-line Access: 2020-11-05

Received: 2020-06-22

Revision Accepted: 2020-08-16

Crosschecked: 2020-10-13

Cited: 0

Clicked: 3053

Citations:  Bibtex RefMan EndNote GB/T7714


Ting Chen


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.11 P.885-896


Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency

Author(s):  Ting Chen, Fan Tong, Xiao-yu Wu, Ling Zhu, Qiu-zi Yi, Jing Zheng, Ru-lai Yang, Zheng-yan Zhao, Xiao-hui Cang, Qiang Shu, Ping-ping Jiang

Affiliation(s):  Division of Medical Genetics and Genomics, The Childrens Hospital, Zhejiang University School of Medicine / National Clinical Research Center for Child Health, Hangzhou 310052, China; more

Corresponding email(s):   shuqiang@zju.edu.cn, ppjiang@zju.edu.cn

Key Words:  Mitochondrial dysfunction, Very-long-chain acyl-CoA dehydrogenase (VLCAD), β, -Oxidation, Molecular dynamics (MD) simulation

Ting Chen, Fan Tong, Xiao-yu Wu, Ling Zhu, Qiu-zi Yi, Jing Zheng, Ru-lai Yang, Zheng-yan Zhao, Xiao-hui Cang, Qiang Shu, Ping-ping Jiang. Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency[J]. Journal of Zhejiang University Science B, 2020, 21(11): 885-896.

@article{title="Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency",
author="Ting Chen, Fan Tong, Xiao-yu Wu, Ling Zhu, Qiu-zi Yi, Jing Zheng, Ru-lai Yang, Zheng-yan Zhao, Xiao-hui Cang, Qiang Shu, Ping-ping Jiang",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency
%A Ting Chen
%A Fan Tong
%A Xiao-yu Wu
%A Ling Zhu
%A Qiu-zi Yi
%A Jing Zheng
%A Ru-lai Yang
%A Zheng-yan Zhao
%A Xiao-hui Cang
%A Qiang Shu
%A Ping-ping Jiang
%J Journal of Zhejiang University SCIENCE B
%V 21
%N 11
%P 885-896
%@ 1673-1581
%D 2020
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2000339

T1 - Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency
A1 - Ting Chen
A1 - Fan Tong
A1 - Xiao-yu Wu
A1 - Ling Zhu
A1 - Qiu-zi Yi
A1 - Jing Zheng
A1 - Ru-lai Yang
A1 - Zheng-yan Zhao
A1 - Xiao-hui Cang
A1 - Qiang Shu
A1 - Ping-ping Jiang
J0 - Journal of Zhejiang University Science B
VL - 21
IS - 11
SP - 885
EP - 896
%@ 1673-1581
Y1 - 2020
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2000339

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.




Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Andresen BS, Olpin S, Poorthuis BJHM, et al., 1999. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet, 64(2):479-494.

[2]Aoyama T, Souri M, Ushikubo S, et al., 1995. Purification of human very-long-chain acyl-coenzyme A dehydrogenase and characterization of its deficiency in seven patients. J Clin Invest, 95(6):2465-2473.

[3]Behrend AM, Harding CO, Shoemaker JD, et al., 2012. Substrate oxidation and cardiac performance during exercise in disorders of long chain fatty acid oxidation. Mol Genet Metab, 105(1):110-115.

[4]Berendsen HJC, Postma JPM, van Gunsteren WF, et al., 1984. Molecular dynamics with coupling to an external bath. J Chem Phys, 81(8):3684-3690.

[5]Bleeker JC, Kok IL, Ferdinandusse S, et al., 2019. Proposal for an individualized dietary strategy in patients with very long-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis, 42(1):159-168.

[6]Boneh A, Andresen BS, Gregersen N, et al., 2006. VLCAD deficiency: pitfalls in newborn screening and confirmation of diagnosis by mutation analysis. Mol Genet Metab, 88(2):166-170.

[7]Bramucci E, Paiardini A, Bossa F, et al., 2012. PyMod: sequence similarity searches, multiple sequence-structure alignments, and homology modeling within PyMOL. BMC Bioinformatics, 13:S2.

[8]Buck MD, O'Sullivan D, Klein Geltink RI, et al., 2016. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell, 166(1):63-76.

[9]Cecatto C, Amaral AU, da Silva JC, et al., 2018. Metabolite accumulation in VLCAD deficiency markedly disrupts mitochondrial bioenergetics and Ca2+ homeostasis in the heart. FEBS J, 285(8):1437-1455.

[10]Essmann U, Perera L, Berkowitz ML, et al., 1995. A smooth particle mesh Ewald method. J Chem Phys, 103(19):8577-8593.

[11]Gillingham MB, Scott B, Elliott D, et al., 2006. Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Mol Genet Metab, 89(1-2):58-63.

[12]Hess B, 2008. P-LINCS: a parallel linear constraint solver for molecular simulation. J Chem Theory Comput, 4(1):116-122.

[13]Hess B, Kutzner C, van der Spoel D, et al., 2008. GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput, 4(3):435-447.

[14]Huang J, Mackerell AD Jr, 2013. CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J Comput Chem, 34(25):2135-2145.

[15]Humphrey W, Dalke A, Schulten K, 1996. VMD: visual molecular dynamics. J Mol Graph, 14(1):33-38.

[16]Jiang PP, Wang M, Xue L, et al., 2016. A hypertension-associated tRNAAla mutation alters tRNA metabolism and mitochondrial function. Mol Cell Biol, 36(14):1920-1930.

[17]Li XY, Ding Y, Ma YY, et al., 2015. Very long-chain acyl-coenzyme A dehydrogenase deficiency in Chinese patients: eight case reports, including one case of prenatal diagnosis. Eur J Med Genet, 58(3):134-139.

[18]Lim SC, Tajika M, Shimura M, et al., 2018. Loss of the mitochondrial fatty acid β-oxidation protein medium-chain acyl-coenzyme A dehydrogenase disrupts oxidative phosphorylation protein complex stability and function. Sci Rep, 8:153.

[19]McAndrew RP, Wang YD, Mohsen AW, et al., 2008. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J Biol Chem, 283(14):9435-9443.

[20]Merritt JL II, Norris M, Kanungo S, 2018. Fatty acid oxidation disorders. Ann Transl Med, 6(24):473.


[22]Miller MJ, Burrage LC, Gibson JB, et al., 2015. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab, 116(3):139-145.

[23]Nomura M, Liu J, Rovira II, et al., 2016. Fatty acid oxidation in macrophage polarization. Nat Immunol, 17(3):216-217.

[24]Obaid A, Nashabat M, Alfadhel M, et al., 2018. Clinical, biochemical, and molecular features in 37 Saudi patients with very long chain acyl CoA dehydrogenase deficiency. In: Morava E, Baumgartner M, Patterson M, et al. (Eds.), JIMD Reports, Volume 40. Springer, Berlin, p.47-53.

[25]Pena LDM, van Calcar SC, Hansen J, et al., 2016. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab, 118(4):272-281.

[26]Philip V, Harris J, Adams R, et al., 2011. A survey of aspartate-phenylalanine and glutamate-phenylalanine interactions in the protein data bank: searching for anion-π pairs. Biochemistry, 50(14):2939-2950.

[27]Schiff M, Mohsen AW, Karunanidhi A, et al., 2013. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab, 109(1):21-27.

[28]Seminotti B, Leipnitz G, Karunanidhi A, et al., 2019. Mitochondrial energetics is impaired in very long-chain acyl-CoA dehydrogenase deficiency and can be rescued by treatment with mitochondria-targeted electron scavengers. Human Mol Genet, 28(6):928-941.

[29]Souri M, Aoyama T, Hoganson G, et al., 1998. Very-long-chain acyl-CoA dehydrogenase subunit assembles to the dimer form on mitochondrial inner membrane. FEBS Lett, 426(2):187-190.

[30]Tong F, Chen T, Jiang PP, et al., 2019. Analysis of ACADVL gene variations among nine neonates with very long chain acyl-CoA dehydrogenase deficiency. Chin J Med Genet, 36(4):310-313 (in Chinese).

[31]Wajner M, Amaral AU, 2015. Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies. Biosci Rep, 36(1):e00281.

[32]Wang YD, Palmfeldt J, Gregersen N, et al., 2019. Mitochondrial fatty acid oxidation and the electron transport chain comprise a multifunctional mitochondrial protein complex. J Biol Chem, 294(33):12380-12391.

[33]Wittig I, Braun HP, Schägger H, 2006. Blue native page. Nat Protoc, 1(1):418-428.

[34]Xiong JH, 2018. Fatty acid oxidation in cell fate determination. Trends Biochem Sci, 43(11):854-857.

[35]Yang JY, Yan RX, Roy A, et al., 2015. The I-TASSER suite: protein structure and function prediction. Nat Methods, 12(1):7-8.

[36]Yu JL, Xiao Y, Liu JX, et al., 2014. Loss of MED1 triggers mitochondrial biogenesis in C2C12 cells. Mitochondrion, 14:18-25.

[37]Zhang DY, Liu ZX, Choi CS, et al., 2007. Mitochondrial dysfunction due to long-chain acyl-CoA dehydrogenase deficiency causes hepatic Steatosis and hepatic insulin resistance. Proc Natl Acad Sci USA, 104(43):17075-17080.

[38]Zhang RN, Li YF, Qiu WJ, et al., 2014. Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency. World J Pediatr, 10(2):119-125.

[39]Zhang YX, Bharathi SS, Beck ME, et al., 2019. The fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase can be a source of mitochondrial hydrogen peroxide. Redox Biol, 26:101253.

[40]Zhao XX, Han JM, Zhu L, et al., 2018. Overexpression of human mitochondrial alanyl-tRNA synthetase suppresses biochemical defects of the mt-tRNAAla mutation in cybrids. Int J Biol Sci, 14(11):1437-1444.

[41]List of electronic supplementary materials

[42]Fig. S1 Variants in VLCAD-deficient patients and their conservation of residues

[43]Fig. S2 Expression levels of HA-tagged VLCAD in cells

[44]Fig. S3 FAO capacity for utilization of exogenous palmitate

[45]Fig. S4 Structural predictions in wild-type and mutant residues

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE