Surviving hypothermia by ferritin-mediated iron detoxification

Abstract

SUMMARYHow 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 Fth1/ferritin. 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.

An mRNA silencing mechanism reliant on the cooperation between REGE-1/Regnase-1 and RLE-1/Roquin-1

“…These results are consistent with the silencing of ets-4 by both proteins. However, we noticed that the extend of cold survival appears to differ between the rege-1(-) ; ets-4(-) and rle-1(-) ; ets-4(-) double mutants, with the former surviving cold even better than wild type (21). It indicates that, in addition to ets-4 co-regulation, RLE-1 and/or REGE-1 may play other roles that do not require their cooperation.…”

“…We previously showed that REGE-1 facilitates the accumulation of body fat and cold resistance by lowering the levels of ETS-4 (Fig. 1A) (14,21). Because RLE-1, like REGE-1, is required for the silencing of ets-4 mRNA, one could expect similar biological functions of both proteins.…”

“…By regulating the levels of ETS-4, REGE-1 controls various aspects of animal physiology, including fat metabolism and cold resistance (Fig. 1A) (14,21). The C. elegans REGE-1 and mammalian Regnase-1 share the same domain organization, suggesting their functional conservation (22).…”