DAF-16/FOXO and PQM-1/GATA factors up-regulate ferritin to promote cold survival upon ETS-4/SPDEF depletion

Animal hibernation is one of great examples of physiological plasticity where by animals enter a hypometabolic state for extended periods of time (Storey and Storey, 2004). This state allows prolonged exposure to cold temperatures without tissue damage. In humans, clinically induced hypothermia has shown protective effects in brain and heart, prolonging damage free survival with low oxygen supply and allowing longer operative time for these patients (Palmers et al., 2015). Although used in the clinic, how hypothermia provides protection in humans is not clear.
Here we use Ceanorhabditis elegans as a genetically tractable model to study cold adaptation. Insulin signaling inhibition and FOXO activation in cold provides protection in both hibernating animals as well as in C. elegans (Savory et al., 2011; Wu and Storey, 2014). We know from previous studies that a conserved ribonuclease REGE-1 is essential for cold survival because it inhibits a transcription factor ETS-4 by degrading mRNA (Habacher et al., 2016). Upon ETS-4 depletion animals subjected to cold adaptation will survive cold temperature longer, by upregulating both DAF-16/FOXO and PQM-1/GATA factors, both known for their role in lifespan extension (Tepper et al., 2013). We show that these two transcription factors converge together to upregulate FTN-1, which sequesters iron from the cell. Iron has a profound role in the cell, besides being a co-factor of many enzymes and essential redox buffer in mitochondria, it is known that it can induce damage by generating reactive oxygen species in the cell (Joppe et al., 2019). In hibernating animals, the oxidative stress response plays a crucial role in preservation of animal tissues and is needed to ensure survival (Yin et al., 2016). Therefore, understanding iron metabolism and its underlying molecular regulation contributes to our understanding of cold adaptation.
We also used C. elegans to uncouple cold adaptation from fat content. This indicates that there are multiple pathways involved in cold adaptation that function independent of body fat.