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

Adaptation and survival in response to diverse stressors involve reprogramming of mRNA translation. Although the cellular response to mild stress has been intensively studied, the response to severe stress remains unclear. We show here that under severe stress conditions, cells induce transient hibernation-like mechanisms in anticipation of recovery, which we have termed the Adaptive Pausing Response (APR). The APR is a coordinated cellular response that limits ATP supply and consumption processes via severe mitochondrial fragmentation and inhibits mRNA translation initiation by induction of ribosome pausing at translation initiation codons, respectively. During recovery from severe stress, cells exhibited adaptive ISR signaling, which permitted cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. We propose that the APR preserves vital elements of cellular function in response to severe environmental stress, and likely plays a major role in homeostasis and pathogenesis. Cells were treated with the appropriate stressor. Ribo-seq and corresponding RNA-seq experiments were performed.