Screening for Mitochondrial tRNA Variants in 200 Patients with Systemic Lupus Erythematosus.

introductionSystemic lupus erythematosus (SLE) is a common autoimmune disease with unknown etiology. Recently, a growing number of evidence suggested that mitochondrial dysfunctions played active roles in the pathogenesis of SLE, but its detailed mechanism remains largely undetermined. The aim of this study was to analyze the frequencies of mitochondrial tRNA (mt-tRNA) variants in Chinese individuals with SLE.

methodsWe carried out a mutational screening of mt-tRNA variants in a cohort of 200 patients with SLE and 200 control subjects by PCR-Sanger sequencing. The potential pathogenicity of mt-tRNA variants was evaluated by phylogenetic conservation and haplogroup analyses. In addition, trans-mitochondrial cybrid cell lines were established, and mitochondrial functions including ATP, reactive oxygen species (ROS), mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential (MMP), superoxide dismutase (SOD), and mt-RNA transcription were analyzed in cybrids with and without these putative pathogenic mt-tRNA variants.

resultsWe identified five possible pathogenic variants: tRNAVal G1606A, tRNALeu(UUR) A3243G, tRNAIle A4295G, tRNAGly T9997C, and tRNAThr A15924G that only found in SLE patients but were absent in controls. Interestingly, these variants were located at extremely conserved nucleotides of the corresponding tRNAs and may alter tRNAs' structure and function. Furthermore, cells carrying these tRNA variants had much lower levels of ATP, mtDNA copy number, MMP, and SOD than controls; by contrast, the levels of ROS increased significantly (p < 0.05 for all). Furthermore, a significant reduction in mt-ND1, ND2, ND3, ND5, and A6 mRNA expression was observed in cells with these mt-tRNA variants, while compared with controls. Thus, failures in tRNA metabolism caused by these variants would impair mitochondrial translation and subsequently lead to mitochondrial dysfunction that was involved in the progression and pathogenesis of SLE.

conclusionsOur study suggested that mt-tRNA variants were important causes for SLE, and screening for mt-tRNA pathogenic variants was recommended for early detection and prevention for this disorder.