Scientists at Columbia University report that they have found that a rare type of lipid is a key driver of ferroptosis, a form of cell death.

The findings provide new details on how cells die during ferroptosis and could improve understanding of how to stop ferroptosis in contexts where it is harmfully occurring as in neurodegenerative diseases or induce it in contexts where it could be useful, such as killing dangerous cancer cells, according to Brent Stockwell, PhD, who led a team of researchers who discovered ferroptosis in 2012.

The study “Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis” appears in Cell and was conducted by professors in Columbia’s department of biological sciences, department of chemistry, and the Columbia University Irving Medical Center.

“Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFA1s) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFA2s) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood,” wrote the investigators.

Key research discovery

“Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFA2s) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFA2s occurred in aging and Huntington’s disease brain tissue, linking it to ferroptosis.”

“Notably, PC-PUFA2s interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA2-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFA2s in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids.”

“PC-PUFA2s may serve as diagnostic and therapeutic targets for modulating ferroptosis.”

The new research found that a rare type of lipid with two polyunsaturated fatty acyl tails, called a diPUFA phospholipid, was present in a range of contexts where ferroptosis was occurring, including in aging brains and Huntington’s disease-affected brain tissue. The finding indicates that the lipid is efficient at promoting ferroptosis.

“The discovery that these diPUFA lipids are important drivers of ferroptosis deepens our understanding of this form of cell death, and these lipids’ role in controlling a cell’s homeostasis in general,” Stockwell said. “Harnessing these lipids may eventually help us identify where ferroptosis has occurred and deliberately manipulate them to either induce cell death or stop it. This can begin to give us both understanding and the power to control cell death.”

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