Mammalian cells have to adapt to environmental challenges that range from mild to severe stress. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe stress conditions, cells induce a transient hibernation-like mechanism that anticipates recovery. We demonstrate that this Adaptive Pausing Response (APR) is a coordinated cellular response that limits ATP supply and consumption though mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery from severe stress. We further show that recovery from severe stress involves adaptive ISR (Integrated Stress Response) signaling that in turn permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress through the APR, a mechanism that preserves vital elements of cellular function under harsh environmental conditions.

中文翻译：

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适应性翻译暂停是细胞对严重环境压力的反应的标志

哺乳动物细胞必须适应从轻度到严重压力的环境挑战。尽管已经广泛研究了细胞对轻度应激的反应，但是细胞如何对重度应激仍然不清楚。我们在这里显示，在严重的压力条件下，细胞会诱导一个短暂的冬眠样机制，有望恢复。我们证明，这种自适应暂停反应（APR）是一种协调的细胞反应，通过线粒体片段化和mRNA翻译的广泛暂停来限制ATP的供应和消耗。这种暂停是通过核糖体停滞在翻译起始密码子上来完成的，这使mRNA保持了从严重压力中恢复后恢复翻译的状态。我们进一步表明，从重度应激中恢复涉及适应性ISR（综合应激反应）信号传导，进而使细胞周期进程，生长恢复和线粒体片段化逆转。我们的发现表明，细胞可以通过APR应对严重的压力，APR是一种在恶劣的环境条件下保留细胞功能至关重要的机制。