Quiñones-Lombraña Adolfo, Blanco Javier G
Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, USA.
Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, USA.
Biochim Biophys Acta. 2015 Jul;1852(7):1420-7. doi: 10.1016/j.bbadis.2015.04.004. Epub 2015 Apr 11.
The regulation of mitochondrial biogenesis is under the control of nuclear genes including the master Mitochondrial Transcription Factor A (TFAM). Recent evidence suggests that the expression of TFAM is regulated by microRNAs (miRNAs) in various cellular contexts. Here, we show that hsa-miR-155-5p, a prominent miRNA encoded in chromosome 21, controls the expression of TFAM at the post-transcriptional level. In human fibroblasts derived from a diploid donor, downregulation of TFAM by hsa-miR-155-5p decreased mitochondrial DNA (mtDNA) content. In contrast, downregulation of TFAM by hsa-miR-155-5p did not decrease mtDNA content in fibroblasts derived from a donor with Down syndrome (DS, trisomy 21). In line, downregulation of mitochondrial TFAM levels through hsa-miR-155-5p decreased mitochondrial mass in diploid fibroblasts but not in trisomic cells. Due to the prevalence of mitochondrial dysfunction and cardiac abnormalities in subjects with DS, we examined the presence of potential associations between hsa-miR-155-5p and TFAM expression in heart samples from donors with and without DS. There were significant negative associations between hsa-miR-155-5p and TFAM expression in heart samples from donors with and without DS. These results suggest that regulation of TFAM by hsa-miR-155-5p impacts mitochondrial biogenesis in the diploid setting but not in the DS setting.
线粒体生物合成的调控受包括主要的线粒体转录因子A（TFAM）在内的核基因控制。最近的证据表明，在各种细胞环境中，TFAM的表达受微小RNA（miRNA）调控。在此，我们表明，位于21号染色体上的一种重要miRNA——hsa-miR-155-5p，在转录后水平控制TFAM的表达。在来自二倍体供体的人成纤维细胞中，hsa-miR-155-5p下调TFAM会降低线粒体DNA（mtDNA）含量。相反，在来自唐氏综合征（DS，21三体）供体的成纤维细胞中，hsa-miR-155-5p下调TFAM并不会降低mtDNA含量。同样，通过hsa-miR-155-5p下调线粒体TFAM水平会降低二倍体成纤维细胞中的线粒体质量，但在三体细胞中则不会。由于DS患者普遍存在线粒体功能障碍和心脏异常，我们检测了有无DS的供体心脏样本中hsa-miR-155-5p与TFAM表达之间潜在关联的存在情况。有无DS的供体心脏样本中，hsa-miR-155-5p与TFAM表达之间均存在显著的负相关。这些结果表明，hsa-miR-155-5p对TFAM的调控在二倍体环境中影响线粒体生物合成，但在DS环境中则不然。
