Identification of genes supporting cold resistance of mammalian cells: lessons from a hibernator
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.
Authors
- Yuta Matsuoka (ORCID: https://orcid.org/0000-0001-9860-3851)
- Rae Maeda
- Kanako Sone
- Masamitsu Sone (ORCID: https://orcid.org/0000-0002-0578-8365)
- Daisuke Anegawa
- Akari Yamauchi (ORCID: https://orcid.org/0000-0002-8973-4443)
- Yuki Sugiura (ORCID: https://orcid.org/0000-0002-6983-8958)
- Yoshifumi Yamaguchi (ORCID: https://orcid.org/0000-0001-7340-4557)
- Sachiyo Enju
- Ryoto Okahashi
- Junpei Yamashita
- Nonoka Mitsuhashi
Institutions
- Hokkaido University of Science (JP)
- Keio University (JP)
- Hokkaido University (JP)
- Kyoto University (JP)
- Hokkaido Bunkyo University (JP)
- Biofuel Research Team (IR)
- Hokkai Gakuen University (JP)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1038/s41419-024-07059-w
- Citations
- 7
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.29
Funders
- Naito Foundation
- Takeda Science Foundation
- Cell Science Research Foundation
- Akiyama Life Science Foundation
- Sumitomo Foundation
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Inamori Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Hokkaido University
- Kitasato University
- Terumo Foundation for Life Sciences and Arts
- Sekisui Chemical
- Nature
- Toray Science Foundation
- Japan Society for the Promotion of Science
- Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences