The mitochondrial Ca2+ uptake regulator, MICU1, is involved in cold stress-induced ferroptosis

Ferroptosis has recently attracted much interest because of its relevance to human diseases such as Cancer and ischemia-reperfusion 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 CA²⁺ 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 CA²⁺ increase, hyperpolarization of the mitochondrial membrane potential (MMP), and subsequent lipid peroxidation under cold stress. Collectively, these findings suggest that the MICU1-dependent mitochondrial CA²⁺ homeostasis-MMP hyperpolarization axis is involved in cold stress-induced lipid peroxidation and Ferroptosis.