Ferritin-mediated iron detoxification promotes hypothermia survival in Caenorhabditis elegans and murine neurons.

How animals rewire cellular programs to survive cold is a fascinating problem with potential biomedical implications, ranging from emergency medicine to space travel. Studying a hibernation-like response in the free-living nematode Caenorhabditis elegans, we uncovered a regulatory axis that enhances the natural resistance of nematodes to severe cold. This axis involves conserved transcription factors, DAF-16/FoxO and PQM-1, which jointly promote cold survival by upregulating FTN-1, a protein related to mammalian ferritin heavy chain (FTH1). Moreover, we show that inducing expression of FTH1 also promotes cold survival of mammalian neurons, a cell type particularly sensitive to deterioration in hypothermia. Our findings in both animals and cells suggest that FTN-1/FTH1 facilitates cold survival by detoxifying ROS-generating iron species. We finally show that mimicking the effects of FTN-1/FTH1 with drugs protects neurons from cold-induced degeneration, opening a potential avenue to improved treatments of hypothermia.

Project POIR.04.04.00-00-203 A/16 was carried out within the Team program of the Foundation for Polish Science, co-financed by the European Union under the European Regional Development Fund. RC was also supported by the EMBO Installation Grant No. 3615, the Polish National Science Center grant 2019/34/A/NZ3/00223, and the Research Council of Norway grant FRIMEDBIO-286499. The research leading to these results has received funding from the Norwegian Financial Mechanism 2014–2021 operated by the Polish National Science Center under the project contract nr UMO-2019/34/H/NZ3/00691. K.S.-K. and M.Fi. were supported by the National Science Center grant 2018/31/B/NZ3/03621