Dihydroxy-Metabolites of Dihomo-gamma-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration

Abstract

Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA, dihomo gamma linolenic acid (DGLA), specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH, representing a new class of lipid metabolite that induces neurodegeneration via ferroptosis.

Quantitative Profiling Method for Oxylipins in Neurodegenerative Diseases by Liquid Chromatography Coupled with Tandem Mass Spectrometry

“…In this study, it is noteworthy to highlight that certain compound, including metabolites derived from DGLA, three distinct isomeric forms of EpEDE, and DHED, were successfully synthesized and comprehensively characterized for the very first time. As a result, the incorporation of these oxylipins in our method enables us to determine these important lipids in C. elegans , like DHED which induces neurodegeneration and ferroptosis, 11 thereby contributing valuable insights to the quantitative lipidomics and targeted metabolomics field.…”

“…18,19 ( Figure 1 ) Our recent study also indicated that dihydroxyeicosadienoic acid (DHED), an epoxide hydrolase metabolite of dihomo-gamma-linolenic acid, induces degeneration of dopaminergic neurons through ferroptosis, which could affect aging. 11 However, the exact role of oxylipins in neurodegeneration and whether they play any critical role in aging remains elusive. 20 Therefore, investigating whether aging has any effects on the oxylipins level and vice versa will help to develop more effective preventative measures and treatments for age-related diseases, including neurodegenerative diseases.…”

“…Recent research showed that dietary lipids have significant effects on aging and cell senescence, [3][4][5] and their downstream oxidized polyunsaturated fatty acid (PUFA) metabolites (namely oxylipins) are key lipid mediators for many disease states including but not limited to, cancer, lupus, cardiovascular [6][7][8] , and neurodegenerative diseases. [9][10][11][12] An increase in the expression of enzymes that produce oxylipins, including, lipoxygenase (LOX) 13 , Cyclooxygenase (COX) 14 soluble epoxide hydrolase (sEH), and microsomal epoxide hydrolase (mEH) is observed in AD compared to healthy individuals. [15][16][17] As a result, endogenous levels of specific oxylipins produced by sEH are upregulated in AD individuals.…”

Ferroptosis: Potential opportunities for natural products in cancer therapy

“…However, dysregulation of ferroptosis can promote the development of multiple human diseases (Y. Jiang, Qiao, et al, 2023;Sarparast et al, 2023;. Researchers have shown increasing enthusiasm for the role of ferroptosis in cancer development.…”

Ironing out Neurodegeneration: New Class of Lipids Promotes Ferroptosis in Dopaminergic Neurons

“…In this issue of ACS Central Science, Alan, Lee, and co-workers report a new class of lipid metabolite that regulates neurodegeneration through ferroptosis. 3 Ferroptosis is a regulated mechanism of cell death that relies on iron and reactive oxygen species to catalyze lipid peroxidation preferentially in polyunsaturated fatty acids (PUFAs, Figure 1A). 4 PUFAs are long-chain fatty acids that contain at least two double bonds and are classified as omega-3 (ω-3) or omega-6 (ω-6) based on the position of the first double bond relative to the methyl carbon.…”