An ATF4-mediated transcriptional adaptation of electron transport chain disturbance primes progenitor cells for proliferation in vivo

ABSTRACT The mitochondrial electron transport chain (ETC) enables many important metabolic reactions, like ATP generation and redox balance. While the vital importance of mitochondrial function is obvious, the cellular response to defects in mitochondria and in particular the modulation of signalling pathway outputs is not understood. Using the Drosophila eye as model, we show that the combination of Notch signalling and a mild attenuation of the ETC via knock-down of COX7a causes massive cellular over-proliferation. The tumour like growth is caused by a transcriptional response through the eIF2α-kinase PERK and ATF4, a stress-induced transcription factor, which activates the expression of many metabolic enzymes, nutrient transporters and mitochondrial chaperones. We find this stress adaptation to be beneficial for progenitor cell fitness upon ETC attenuation. Activation of the ATF4 mediated stress response renders cells sensitive to proliferation induced by the growth-promoting Notch or Ras signalling pathways, leading to severe tissue over-growth. In sum, our results suggest ETC function is monitored by the PERK-ATF4 pathway, a cellular adaptation hijacked by growth-promoting signalling pathways in situations of oncogenic pathway activity.