The mitochondrial Ca ²⁺ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis

Abstract

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.

A vinyl-decorated covalent organic framework for ferroptotic cancer therapy via visible-light-triggered cysteine depletion

“…It is widely known that MMP controls adenosine triphosphate (ATP) synthesis and ROS generation and is itself controlled by the mitochondrial tricarboxylic acid cycle and respiratory chain. 60 In theory, both enhanced ATP synthesis and increased leakage of mitochondrial ROS from the respiratory chain lead to MMP hyperpolarization. Experimentally, chemiluminescence-based ATP measurements revealed that, for HCT-116 cells that were pretreated with Ru( ii )@COF-V for 2 h, cysteine depletion caused by exposure to a blue LED significantly reduced intracellular ATP.…”

Natural product manoalide promotes EGFR-TKI sensitivity of lung cancer cells by KRAS-ERK pathway and mitochondrial Ca2+ overload-induced ferroptosis

“…Activation of mitochondrial Ca 2+ signaling promotes cystine addiction and sensitizes PDAC cells to ferroptosis (Nakamura et al, 2021). However, there was no report on the specific mechanism of mitochondrial Ca 2+ imbalance-induced ferroptosis.…”

Organelle-Specific Mechanisms in Crosstalk between Apoptosis and Ferroptosis

“…ER-to-mitochondrion Ca 2+ transfer via MAMs is involved in apoptosis regulation [ 126 ]. Similarly, mitochondrial Ca 2+ uptake regulator 1 (MICU1) was found to regulate cold stress-induced ferroptosis in A549 cells [ 127 ]. Despite the paucity of research on MAMs and ferroptosis, Ca 2+ release from the ER into the cytoplasm increases during ferroptosis [ 95 ].…”