Sorge, S. | Search bioRxiv

bioRxiv2024

A Drosophila holidic diet optimised for growthand development

Diets composed of chemically pure components (holidic diets) are useful for determining the metabolic roles of individual nutrients. For the model organism Drosophila melanogaster, existing holidic diets are unable to support rapid growth characteristic of the larval stage. Here, we use a nutrient co-optimisation strategy across more than 50 diet variants to design HoldFast, a holidic medium tailored to fast larval growth and development. We identify dietary amino acid ratios optimal for developmental speed but show that they compromise survival unless vitamins and sterols are co-optimised. Rapid development on HoldFast is not improved by adding fatty acids but it is dependent upon their de novo synthesis in the fat body via fatty acid synthase (FASN). HoldFast outperforms other holidic diets, supporting rates of growth and development close to those of yeast-based diets and, under germ-free conditions, identical. HoldFast provides new opportunities for studying growth and metabolism during Drosophila development.

developmental biology↗

bioRxiv2018

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

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 eIF2-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.

developmental biology↗