image: 8HQ/FAC treatment increases the intercellular labile iron; labile iron induces Mitochondrial ROS production and increases membrane permeability that results in Ca2+ influx. Excessive Ca2+ in cytoplasm activates calpain-1 and results in rearrangement of cytoskeleton. Meanwhile, excessive Ca2+ uptake of mitochondrion leads to mitochondrial swelling and large bubbles blowing from the plasma, which exhibits the feature of oncotic cell death. While, the nucleus undergoes pycnosis and chromatin condensation, which exhibits the feature of apoptosis. The inhibitor of mitochondrial calcium uniporter (MCU), such as DS16570511 and MCU-i4, can inhibit Ca2+ uptake of mitochondria and prevent the ferroptosis induced by labile iron. view more
Credit: ©Science China Press
This study is led by Dr. Anjian Xu (Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University), Dr. Min Cong (Liver Research Center, Beijing Friendship Hospital, Capital Medical University) and Dr. Junying Ding (Beijing Key Laboratory of Basic Research with Traditional Chinese Medicine on Infectious Diseases, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University). The team found a novel iron-dependent form of ferroptosis induced by intercellular labile iron, which was distinct from canonical ferroptosis, and they named it as labile iron–induced ferroptosis.
They found that, although canonical ferroptosis and labile iron–induced ferroptosis shared some features, such as elevated reactive oxygen species (ROS), lipid peroxidation and could be rescued by iron chelators such as DFO, the mechanisms regulating these two forms of ferroptosis were different. Notably, mitochondria played a central role in labile iron–induced ferroptosis. Specifically, mitochondrial ROS production was induced by labile iron, and mitochondrial calcium uptake determined the fate of the mitochondria and the cells. In addition, they found that cells undergoing labile iron–induced ferroptosis exhibited cytoplasmic features of oncosis and nuclear features of apoptosis. Furthermore, labile iron–induced ferroptosis involved a unique set of genes that were also involved in apoptosis and necrosis. Finally, labile iron–induced ferroptosis was observed in liver subjected to acute iron overload in vivo.
This study provides a new basis for enriching the mechanism of iron death, improving the relevant theory of iron death, and developing new therapeutic targets for ferroptosis.
See the article:
An iron-dependent form of non-canonical ferroptosis induced by labile iron
https://doi.org/10.1007/s11427-022-2244-4
Journal
Science China Life Sciences