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Abstract Susceptibility of human cells to cold stress restricts the use of therapeutic hypothermia and long-term preservation of organs at low temperatures. In contrast, cells of mammalian hibernators possess remarkable cold resistance, but little is known about the molecular mechanisms underlying this phenomenon. In this study, we conducted a gain-of-function screening of genes that confer cold resistance to cold-vulnerable human cells using a cDNA library constructed from the Syrian hamster, a mammalian hibernator, and identified Gpx4 as a potent suppressor of cold-induced cell death. Additionally, genetic deletion of or pharmacological inhibition of Gpx4 revealed that Gpx4 is necessary for suppressing lipid peroxidation specifically under cold in hamster cell lines. Genetic disruption of other ferroptosis-suppressing pathways, namely biopterin synthesis and mitochondrial or plasma membrane CoQ reduction pathways, also accelerated cold-induced cell death under Gpx4 dysfunction. Collectively, ferroptosis-suppressing pathways protect the cells of a mammalian hibernator from cold-induced cell death and the augmentation of these pathways renders cold resistance to cells of non-hibernators, including humans.

Abstract The underlying mechanisms of atherosclerosis, the second leading cause of death among Werner syndrome (WS) patients, are not fully understood. Here, we establish an in vitro co-culture system using macrophages (iMφs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. In co-culture, WS-iMφs induces endothelial dysfunction in WS-iVECs and characteristics of the synthetic phenotype in WS-iVSMCs. Transcriptomics and open chromatin analysis reveal accelerated activation of type I interferon signaling and reduced chromatin accessibility of several transcriptional binding sites required for cellular homeostasis in WS-iMφs. Furthermore, the H3K9me3 levels show an inverse correlation with retrotransposable elements, and retrotransposable element-derived double-stranded RNA activates the DExH-box helicase 58 (DHX58)-dependent cytoplasmic RNA sensing pathway in WS-iMφs. Conversely, silencing type I interferon signaling in WS-iMφs rescues cell proliferation and suppresses cellular senescence and inflammation. These findings suggest that Mφ-specific inhibition of type I interferon signaling could be targeted to treat atherosclerosis in WS patients.

Most mammals adapt thermal physiology around 37°C and large deviations from their range, as observed in severe hypothermia and hyperthermia, resulting in organ dysfunction and individual death. A prominent exception is mammalian hibernation. Mammalian hibernators resist the long-term duration of severe low body temperature that is lethal to non-hibernators, including humans and mice. This cold resistance is supported, at least in part, by intrinsic cellular properties, since primary or immortalized cells from several hibernator species can survive longer than those from non-hibernators when cultured at cold temperatures. Recent studies have suggested that cold-induced cell death fulfills the hallmarks of ferroptosis, a type of necrotic cell death that accompanies extensive lipid peroxidation by iron-ion-mediated reactions. In this review, we summarize the current knowledge of cold resistance of mammalian hibernators at the cellular and molecular levels to organ and systemic levels and discuss key pathways that confer cold resistance in mammals.

Most mammals adapt thermal physiology around 37°C and large deviations from their range, as observed in severe hypothermia and hyperthermia, resulting in organ dysfunction and individual death. A prominent exception is mammalian hibernation. Mammalian hibernators resist the long-term duration of severe low body temperature that is lethal to non-hibernators, including humans and mice. This cold resistance is supported, at least in part, by intrinsic cellular properties, since primary or immortalized cells from several hibernator species can survive longer than those from non-hibernators when cultured at cold temperatures. Recent studies have suggested that cold-induced cell death fulfills the hallmarks of ferroptosis, a type of necrotic cell death that accompanies extensive lipid peroxidation by iron-ion-mediated reactions. In this review, we summarize the current knowledge of cold resistance of mammalian hibernators at the cellular and molecular levels to organ and systemic levels and discuss key pathways that confer cold resistance in mammals. [ABSTRACT FROM AUTHOR]