Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.
Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.
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DOI：
10.1038/gim.2017.251
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Horvath R
中科院分区：
文献类型：
--
作者：
Boczonadi V;King MS;Smith AC;Olahova M;Bansagi B;Roos A;Eyassu F;Borchers C;Ramesh V;Lochmüller H;Polvikoski T;Whittaker RG;Pyle A;Griffin H;Taylor RW;Chinnery PF;Robinson AJ;Kunji ERS;Horvath R
线粒体载体家族（SLC 25）的成员跨线粒体内膜转运代谢物、核苷酸、辅因子和无机离子。我们通过全外显子组测序鉴定了一例患者的一种新型线粒体载体基因的致病性变异。通过转运试验、计算机建模、随后的靶向代谢试验以及在人成纤维细胞和神经元中的体外研究来研究突变的致病性。患者携带纯合致病性变体c.695A>G; p. SLC 25 A21基因编码线粒体氧代二羧酸载体，在SLC 25 A21基因中（Lys 232 Arg）缺失，并发展为脊髓性肌萎缩症和线粒体肌病。转运试验表明，突变使SLC 25 A21功能障碍，2-氧代己二酸不能输入到线粒体基质。中枢代谢的计算机模型预测，氧代二羧酸转运受损会破坏赖氨酸和色氨酸降解的途径，并导致2-氧代己二酸、哌啶酸和喹啉酸的积累，这在患者的尿液中得到了靶向代谢组学的证实。暴露于2-氧代己二酸和喹啉酸降低神经元细胞（SH-SY 5 Y）的线粒体复合物的水平，并诱导细胞凋亡。线粒体氧代二羧酸载体缺乏导致线粒体功能障碍和氧代己二酸和喹啉酸的积累，这反过来又引起脊髓运动神经元的毒性，导致脊髓肌肉萎缩样疾病。
Members of the mitochondrial carrier family (SLC25) transport metabolites, nucleotides, co-factors and inorganic ions across the mitochondrial inner membrane. We identified a pathogenic variant in a novel mitochondrial carrier gene in a patient by whole exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modelling followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons. The patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid and quinolinic acid, which was confirmed in the patient’s urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis. Mitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease.
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影响因子：
30.8
作者：
Abrams AJ;Hufnagel RB;Rebelo A;Zanna C;Patel N;Gonzalez MA;Campeanu IJ;Griffin LB;Groenewald S;Strickland AV;Tao F;Speziani F;Abreu L;Schüle R;Caporali L;La Morgia C;Maresca A;Liguori R;Lodi R;Ahmed ZM;Sund KL;Wang X;Krueger LA;Peng Y;Prada CE;Prows CA;Schorry EK;Antonellis A;Zimmerman HH;Abdul-Rahman OA;Yang Y;Downes SM;Prince J;Fontanesi F;Barrientos A;Németh AH;Carelli V;Huang T;Zuchner S;Dallman JE
通讯作者：
Dallman JE
影响因子：
3.7
作者：
Braidy, Nady;Grant, Ross;Guillemin, Gilles J.
通讯作者：
Guillemin, Gilles J.
影响因子：
14.8
作者：
Becker, Scott A.;Feist, Adam M.;Herrgard, Markus J.
通讯作者：
Herrgard, Markus J.
影响因子：
4.2
作者：
Palmieri, Ferdinando
通讯作者：
Palmieri, Ferdinando
影响因子：
3.6
作者：
GOVAERTS, L;MONNENS, L;VANRAAYSELTEN, A
通讯作者：
VANRAAYSELTEN, A