Department of Biochemistry, Ajou University School of Medicine, Suwon 16499, Korea.
Department of Biomedical Sciences, Graduate School, Ajou University, Suwon 16499, Korea.
Cells. 2022 Jun 30;11(13):2079. doi: 10.3390/cells11132079.
While mitochondrial bioenergetic deregulation has long been implicated in cellular senescence, its mechanistic involvement remains unclear. By leveraging diverse mitochondria-related gene expression profiles derived from two different cellular senescence models of human diploid fibroblasts, we found that the expression of mitoribosomal proteins (MRPs) was generally decreased during the early-to-middle transition prior to the exhibition of noticeable SA-β-gal activity. Suppressed expression patterns of the identified senescence-associated MRP signatures (SA-MRPs) were validated in aged human cells and rat and mouse skin tissues and in aging mouse fibroblasts at single-cell resolution. TIN2- and POT1-interaction protein (TPP1) was concurrently suppressed, which induced senescence, accompanied by telomere DNA damage. Lastly, we show that SA-MRP deregulation could be a potential upstream regulator of TPP1 suppression. Our results indicate that mitoribosomal deregulation could represent an early event initiating mitochondrial dysfunction and serve as a primary driver of cellular senescence and an upstream regulator of shelterin-mediated telomere deprotection.
虽然线粒体生物能量失调长期以来一直与细胞衰老有关，但其中的机制仍不清楚。通过利用源自两种不同人类二倍体成纤维细胞衰老模型的不同线粒体相关基因表达谱，我们发现 mitoribosomal 蛋白 (MRP) 的表达在明显 SA-β-gal 活性出现之前的早期到中期过渡期间通常会下降。鉴定出的与衰老相关的 MRP 特征 (SA-MRPs) 的受抑制表达模式在衰老的人类细胞以及大鼠和小鼠皮肤组织以及衰老的小鼠成纤维细胞中在单细胞分辨率下得到了验证。TIN2 和 POT1 相互作用蛋白 (TPP1) 也同时受到抑制，这会诱导衰老，并伴有端粒 DNA 损伤。最后，我们表明 SA-MRP 失调可能是 TPP1 抑制的潜在上游调节剂。我们的研究结果表明，线粒体核糖体失调可能是引发线粒体功能障碍的早期事件，并作为细胞衰老的主要驱动因素以及 shelterin 介导的端粒去保护的上游调节剂。
