Ferroptosis has recently attracted much interest because of its relevance to human diseases such as cancer and ischemiareperfusion injury. We have reported that prolonged severe cold stress induces lipid peroxidation-dependent ferroptosis, but the upstream mechanism remains unknown. Here, using genome-wide CRISPR screening, we found that a mitochondrial Ca 2+ uptake regulator, mitochondrial calcium uptake 1 (MICU1), is required for generating lipid peroxide and subsequent ferroptosis under cold stress. Furthermore, the gatekeeping activity of MICU1 through mitochondrial calcium uniporter (MCU) is suggested to be indispensable for cold stress-induced ferroptosis. MICU1 is required for mitochondrial Ca 2+ increase, hyperpolarization of the mitochondrial membrane potential (MMP), and subsequent lipid peroxidation under cold stress. Collectively, these findings suggest that the MICU1-dependent mitochondrial Ca 2+ homeostasis-MMP hyperpolarization axis is involved in cold stress-induced lipid peroxidation and ferroptosis.

VCells are constantly exposed to various types of stress, and disruption of the proper response leads to a variety of diseases. Among them, inflammation and apoptosis are important examples of critical responses and should be tightly regulated, as inappropriate control of these responses is detrimental to the organism. In several disease states, these responses are abnormally regulated, with adverse effects. Apoptosis signal-regulating kinase (ASK) family members are stress-responsive kinases that regulate inflammation and apoptosis after a variety of stimuli, such as oxidative stress and endoplasmic reticulum stress. In this review, we summarize recent reports on the ASK family in terms of their involvement in inflammatory diseases, focussing on upstream stimuli that regulate ASK family members.