CLOCK regulates Drp1 mRNA stability and mitochondrial homeostasis by interacting with PUF60
CLOCK regulates Drp1 mRNA stability and mitochondrial homeostasis by interacting with PUF60
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CLOCK 通过与 PUF60 相互作用调节 Drp1 mRNA 稳定性和线粒体稳态
DOI：
10.1016/j.celrep.2022.110635
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发表时间：
2022
期刊：
影响因子：
8.8
通讯作者：
Chao Lu
中科院分区：
文献类型：
--
作者：
Lirong Xu;Jiaxin Lin;Yutong Liu;Bingxuan Hua;Qianyun Cheng;Changpo Lin;Zuoqin Yan;Yaping Wang;Ning Sun;Ruizhe Qian;Chao Lu
Clock、Bmal1、Cryptochrome1/2、Period1/2/3等昼夜节律基因构成了精确的昼夜节律系统。 ClockΔ19是一种常用的小鼠模型，含有生物钟基因突变，缺乏EXON-19编码的51个氨基酸。此前的报告显示，ClockΔ19小鼠存在严重的代谢异常。在这里，我们报告 ClockΔ19 小鼠的线粒体表现出过度裂变和功能障碍。我们还证明了CLOCK通过其EXON 19与RNA结合蛋白PUF60结合。此外，我们发现PUF60通过调节Drp1 mRNA稳定性直接维持线粒体稳态，而与CLOCK的结合可以竞争性抑制这一功能。在 ClockΔ19 小鼠中，CLOCKΔ19 释放 PUF60，导致 Drp1 mRNA 稳定性增强和持久的线粒体裂变。我们的结果揭示了 CLOCK 通过 Drp1 mRNA 稳定性调节线粒体稳态的直接转录后作用，并且 ClockΔ19 小鼠中 CLOCK 外显子 19 的丢失会导致严重的线粒体稳态紊乱。
Circadian genes such as Clock, Bmal1, Cryptochrome1/2, and Period1/2/3 constitute the precise circadian system. ClockΔ19is a commonly used mouse model harboring a circadian clock gene mutation, which lacks the EXON-19-encoded 51 amino acids. Previous reports have shown that ClockΔ19mice have severe metabolic abnormalities. Here, we report that the mitochondria of ClockΔ19mice exhibit excessive fission and dysfunction. We also demonstrate that CLOCK binds to the RNA-binding protein PUF60 through its EXON 19. Further, we find that PUF60 directly maintains mitochondrial homeostasis through regulating Drp1 mRNA stability, while the association with CLOCK can competitively inhibit this function. In ClockΔ19mice, CLOCKΔ19releases PUF60, leading to enhanced Drp1 mRNA stability and persistent mitochondrial fission. Our results reveal a direct post-transcriptional role of CLOCK in regulating mitochondrial homeostasis via Drp1 mRNA stability and that the loss of EXON 19 of CLOCK in ClockΔ19mice leads to severe mitochondrial homeostasis disorders.