PURPOSE To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease. METHODS We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons. RESULTS 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. CONCLUSION 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.

中文翻译：

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线粒体氧代二羧酸盐载体缺乏与线粒体 DNA 耗竭和脊髓性肌萎缩样疾病有关。

目的 了解线粒体氧代二羧酸盐载体 (SLC25A21) 在脊髓性肌萎缩样疾病发展中的作用。方法 我们通过全外显子组测序在一名患者中鉴定出一种新的致病变异。该突变的致病性通过转运分析、计算机建模、靶向代谢测试以及人成纤维细胞和神经元的体外研究进行了研究。结果患者携带纯合致病变异c.695A>G；p.(Lys232Arg) 在 SLC25A21 基因中，编码线粒体氧代二羧酸载体，并发展为脊髓性肌萎缩和线粒体肌病。转运分析表明，该突变导致 SLC25A21 功能失调，并且 2-氧代己二酸不能导入线粒体基质。中枢代谢的计算机模型预测，氧代二羧酸盐的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、哌可酸和喹啉酸的积累，靶向代谢组学在患者的尿液中证实了这一点。暴露于 2-氧代己二酸和喹啉酸会降低神经元细胞 (SH-SY5Y) 中线粒体复合物的水平并诱导细胞凋亡。结论 线粒体氧代二羧酸载体缺乏会导致线粒体功能障碍和氧代己二酸和喹啉酸的积累，进而导致脊髓运动神经元毒性，导致脊髓性肌萎缩样疾病。通过靶向代谢组学在患者的尿液中证实了这一点。暴露于 2-氧代己二酸和喹啉酸会降低神经元细胞 (SH-SY5Y) 中线粒体复合物的水平并诱导细胞凋亡。结论 线粒体氧代二羧酸载体缺乏会导致线粒体功能障碍和氧代己二酸和喹啉酸的积累，进而导致脊髓运动神经元毒性，导致脊髓性肌萎缩样疾病。通过靶向代谢组学在患者的尿液中证实了这一点。暴露于 2-氧代己二酸和喹啉酸会降低神经元细胞 (SH-SY5Y) 中线粒体复合物的水平并诱导细胞凋亡。结论 线粒体氧代二羧酸载体缺乏会导致线粒体功能障碍和氧代己二酸和喹啉酸的积累，进而导致脊髓运动神经元毒性，导致脊髓性肌萎缩样疾病。