Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress

To survive, mammalian cells must adapt to environmental challenges. 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 hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through 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. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions. [Display omitted] •Cells exposed to extremely harsh environments preserve the ability to recover•Severe stress induces dramatic mitochondrial fragmentation•Severe stress induces a hibernation-like state entailing ribosome pausing•Exit from the hibernation-like state requires induction of ISR Jobava et al. show that near-lethal environmental stress induces a hibernation-like state of severe mitochondrial fragmentation with 80S ribosomes stalled at the start codons of a select group of mRNAs. Induction of ISR during removal of stress reverses the hibernation-like state and promotes a return to homeostasis.