A multidisciplinary international team of scientists solved the mystery of a recently discovered type of controlled cell death, mapping the path to potential therapies for conditions ranging from radiation injury to cancer. The study, led in part by the University of Pittsburgh, is reported today in two papers in Nature Chemical Biology.
Ferroptosis is a way the body uses iron (which is "ferro" in Latin) to catalyze a reaction that safely destroys and recycles a malfunctioning or damaged cell. Until this study, scientists didn't know how the body signaled - within the damaged cell and to other cells - that this well-regulated death needed to occur.
Ferroptosis is characterized by accumulation of lipid peroxidation products and lethal ROS, but the source and identity of lipid death signals that cause toxicity are poorly defined.
Through two years of experiments bridging fields ranging from public health and critical care medicine to basic biology and chemistry, the team analyzed hundreds of molecular combinations generated in the ferroptotic process to discover that only four molecules actually signal for the cell to die. All four are phospholipids - naturally occurring molecules that make up cell membranes.
Researchers uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4–Acsl4 double-knockout cells showed marked resistance to ferroptosis.
Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis.
Researchers also discovered in the second paper that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls—arachidonoyl (AA) and adrenoyl (AdA).
Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E.
."More and more, we're appreciating that the damage from acute radiation is happening to the lining of the intestine, and that damage triggers a cascade of health complications that lead to sepsis, a very deadly syndrome," said another author. "We believe that the radiation is triggering ferroptosis in the cells that line the intestine. If we can stop that process and get the body to repair, rather than systematically destroy, those cells, we might save the victims of devastating dirty bomb attacks."
Conversely, in cancer, the body is failing to destroy dysfunctional cancer cells, allowing tumors to grow unchecked. By understanding the ferroptotic pathway, the researchers hope to find medications that can prompt it to recognize and kill cancer cells.
http://www.upmc.com/media/NewsReleases/2016/Pages/kaganbayir-nature-ferroptotic.aspx
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