Objectives: Dilated cardiomyopathy (DCM) is a complex cardiovascular disease with unknown etiology. Although nuclear genes play active roles in DCM, mitochondrial dysfunction was believed to be involved in the pathogenesis of DCM. The objective of this study was to analyze the association between mitochondrial tRNA (mt-tRNA) mutations and DCM. Materials and Methods: We performed a mutational analysis of mt-tRNA genes in a cohort of 318 patients with DCM and 200 age- and gender-matched control subjects. To further assess their pathogenicity, phylogenetic analysis and mitochondrial functions including mtDNA copy number, ATP, and ROS were analyzed. Results: Seven possible pathogenic mutations, i.e., MT-TL1 3302A#x3e;G, MT-TI 4295A#x3e;G, MT-TM 4435A#x3e;G, MT-TA 5655T#x3e;C, MT-TH 12201T#x3e;C, MT-TE 14692A#x3e;G, and MT-TT 15927G#x3e;A, were identified in the DCM group but were absent in controls. These mutations occurred at extremely conserved nucleotides of corresponding tRNAs and led to the failure in tRNAs metabolism. Moreover, a significant reduction in ATP and mtDNA copy number and a marked increase in ROS level were observed in polymononuclear leukocytes (PMNs) derived from the DCM patients carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for DCM. Conclusions: Our data indicated that mt-tRNA mutations may be the molecular basis for DCM, which provides novel insights into the pathophysiology of DCM that manifested as mitochondrial dysfunction.
Hum Hered 2022;87:1–11

中文翻译：

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318例扩张型心肌病患者线粒体tRNA突变筛查

目的：扩张型心肌病（DCM）是一种病因不明的复杂心血管疾病。尽管核基因在 DCM 中发挥积极作用，但线粒体功能障碍被认为与 DCM 的发病机制有关。本研究的目的是分析线粒体 tRNA (mt-tRNA) 突变与 DCM 之间的关联。材料和方法：我们对 318 名 DCM 患者和 200 名年龄和性别匹配的对照受试者进行了 mt-tRNA 基因突变分析。为了进一步评估它们的致病性，分析了系统发育分析和线粒体功能，包括 mtDNA 拷贝数、ATP 和 ROS。结果：7种可能的致病突变，即MT-TL1 3302A#x3e;G、MT-TI 4295A#x3e;G、MT-TM 4435A#x3e;G、MT-TA 5655T#x3e;C、MT-TH 12201T#x3e; C、MT-TE 14692A#x3e；G 和 MT-TT 15927G#x3e；A，在 DCM 组中被识别，但在对照组中不存在。这些突变发生在相应 tRNA 极其保守的核苷酸处，并导致 tRNA 代谢失败。此外，在来自携带这些 mt-tRNA 突变的 DCM 患者的多单核白细胞 (PMN) 中观察到 ATP 和 mtDNA 拷贝数的显着减少和 ROS 水平的显着增加，这表明这些突变可能导致线粒体功能障碍，从而导致DCM。结论：我们的数据表明，mt-tRNA 突变可能是 DCM 的分子基础，这为 DCM 表现为线粒体功能障碍的病理生理学提供了新的见解。
嗡嗡声 2022 年；87:1–11