PDF(Pubmed)
Abstract：
In addition to mitochondrial DNA, mitochondrial double-stranded RNA (mtdsRNA) is exported from mitochondria. However, specific channels for RNA transport have not been demonstrated. Here, we begin to characterize channel candidates for mtdsRNA export from the mitochondrial matrix to the cytosol. Down-regulation of SUV3 resulted in the accumulation of mtdsRNAs in the matrix, whereas down-regulation of PNPase resulted in the export of mtdsRNAs to the cytosol. Targeting experiments show that PNPase functions in both the intermembrane space and matrix. Strand-specific sequencing of the double-stranded RNA confirms the mitochondrial origin. Inhibiting or down-regulating outer membrane proteins VDAC1/2 and BAK/BAX or inner membrane proteins PHB1/2 strongly attenuated the export of mtdsRNAs to the cytosol. The cytosolic mtdsRNAs subsequently localized to large granules containing the stress protein TIA-1 and activated the type 1 interferon stress response pathway. Abundant mtdsRNAs were detected in a subset of non-small-cell lung cancer cell lines that were glycolytic, indicating relevance in cancer biology. Thus, we propose that mtdsRNA is a new damage-associated molecular pattern that is exported from mitochondria in a regulated manner.
摘要：
除了线粒体DNA,线粒体双链RNA(mtdsRNA)从线粒体输出。然而,RNA转运的特异性通道尚未得到证实。这里,我们开始表征mtdsRNA从线粒体基质输出到细胞质的通道候选物。SUV3的下调导致mtdsRNAs在基质中的积累，而PNPase的下调导致mtdsRNA输出到细胞质。靶向实验表明，PNPase在膜间空间和基质中起作用。双链RNA的链特异性测序证实了线粒体起源。抑制或下调外膜蛋白VDAC1/2和BAK/BAX或内膜蛋白PHB1/2强烈减弱mtdsRNA向细胞质的输出。细胞溶质mtdsRNA随后定位于含有应激蛋白TIA-1的大颗粒并激活1型干扰素应激反应途径。大量的mtdsRNAs在非小细胞肺癌细胞系中检测到，表明与癌症生物学的相关性。因此，我们认为mtdsRNA是一种新的损伤相关分子模式，以调节的方式从线粒体输出。
