Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015, Lausanne, Switzerland.
Mol Cell. 2019 Feb 21;73(4):775-787.e10. doi: 10.1016/j.molcel.2018.11.034. Epub 2019 Jan 11.
Little information is available about how post-transcriptional mechanisms regulate the aging process. Here, we show that the RNA-binding protein Pumilio2 (PUM2), which is a translation repressor, is induced upon aging and acts as a negative regulator of lifespan and mitochondrial homeostasis. Multi-omics and cross-species analyses of PUM2 function show that it inhibits the translation of the mRNA encoding for the mitochondrial fission factor (Mff), thereby impairing mitochondrial fission and mitophagy. This mechanism is conserved in C. elegans by the PUM2 ortholog PUF-8. puf-8 knock-down in old nematodes and Pum2 CRISPR/Cas9-mediated knockout in the muscles of elderly mice enhances mitochondrial fission and mitophagy in both models, hence improving mitochondrial quality control and tissue homeostasis. Our data reveal how a PUM2-mediated layer of post-transcriptional regulation links altered Mff translation to mitochondrial dynamics and mitophagy, thereby mediating age-related mitochondrial dysfunctions.
关于转录后机制如何调节衰老过程的信息很少。在这里，我们表明，RNA 结合蛋白 Pumilio2（PUM2）是一种翻译抑制剂，它在衰老时被诱导，并作为寿命和线粒体动态平衡的负调节剂。PUM2 功能的多组学和跨物种分析表明，它抑制编码线粒体分裂因子（Mff）的 mRNA 的翻译，从而损害线粒体分裂和线粒体自噬。在秀丽隐杆线虫中，这种机制由 PUM2 同源物 PUF-8 保守。在年老线虫中敲低 puf-8 和在老年小鼠的肌肉中进行 Pum2 CRISPR/Cas9 介导的敲除，增强了这两种模型中的线粒体分裂和线粒体自噬，从而改善了线粒体质量控制和组织动态平衡。我们的数据揭示了 PUM2 介导的转录后调节层如何将 Mff 翻译的改变与线粒体动力学和线粒体自噬联系起来，从而介导与年龄相关的线粒体功能障碍。
