Researchers have discovered that certain naturally occurring estrogen metabolites, called catechol estrogens, can powerfully protect neuronal cells against a form of cell death called ferroptosis. This is an important finding, as ferroptosis has been linked to various neurodegenerative diseases. The study revealed that catechol estrogens, such as 2-hydroxyestrone, 2-hydroxyestradiol, 4-hydroxyestrone, and 4-hydroxyestradiol, can directly bind to and inhibit a key cellular enzyme called protein disulfide isomerase (PDI). This prevents PDI from activating nitric oxide synthase, ultimately blocking the accumulation of toxic substances like nitric oxide, reactive oxygen species, and lipid-reactive oxygen species – which are hallmarks of ferroptosis. These findings offer new insights into the estrogen receptor-independent mechanisms by which endogenous estrogen metabolites can protect neuronal cells.
Ferroptosis: A Unique Form of Cell Death
Ferroptosis is a recently discovered form of regulated cell death that is characterized by the excessive accumulation of cellline’>HT22 mouse hippocampal neuronal cells against ferroptosis induced by the chemicals erastin and RSL3.
Mechanism of Protection: Targeting Protein Disulfide Isomerase
The researchers discovered that the key mechanism by which catechol estrogens protect against ferroptosis is through their direct binding and inhibition of the enzyme protein disulfide isomerase (PDI). PDI plays a crucial role in mediating the conversion of nitric oxide synthase (NOS) enzymes from their monomeric to dimeric forms, which leads to the accumulation of nitric oxide, reactive oxygen species, and lipid-ROS – all of which contribute to ferroptotic cell death.
Interestingly, the researchers found that the parent hormones estrone (E1) and estradiol (E2) did not exhibit a similarly strong protective effect against ferroptosis, and the monomethylated metabolites of these estrogens also showed weaker protection compared to the catechol estrogens.
Implications and Future Directions
These findings suggest that the balance between the levels of endogenous estrogens and their catechol metabolites may play an important role in an individual’s susceptibility to neurodegenerative diseases associated with ferroptosis. Further investigations are needed to understand how alterations in the metabolic conversion of estrogens to their catechol derivatives may influence the risk of developing these conditions.
Overall, this study provides valuable insights into the estrogen receptor-independent mechanisms by which endogenous estrogen metabolites, particularly the catechol estrogens, can protect neuronal cells against ferroptosis-mediated cell death. This knowledge may pave the way for the development of new therapeutic strategies targeting ferroptosis in the treatment of various neurodegenerative disorders.
Author credit: This article is based on research by Xuanqi Huang, Ming-Jie Hou, Bao Ting Zhu.
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