Summary: Researchers have identified an enzyme that plays a role in generating the signal that initiates cell death in ferroptosis.
Source: Helmholtz Zentrum München.
Ferroptosis is a recently discovered form of cell death, which is still only partially understood. Scientists at the Helmholtz Zentrum München have now identified an enzyme that plays a key role in generating the signal that initiates cell death. Their findings, published in two articles in the journal Nature Chemical Biology, could now give new impetus to research into the fields of cancer, neurodegeneration and other degenerative diseases.
The term ferroptosis was first coined in 2012. It is derived from the Greek word ptosis, meaning “a fall”, and ferrum, the Latin word for iron, and describes a form of regulated necrotic cell death in which iron appears to play an important role. “The individual mechanisms involved in this type of cell death remain only partly understood, and our findings make an important contribution towards a better understanding of ferroptotic cell death,” says study leader Dr. Marcus Conrad, who is heading a research group at the Institute of Developmental Genetics at the Helmholtz Zentrum München.
Along with his team and colleagues from the University of Pittsburgh, he was able to show that ACSL4*, an enzyme involved in the metabolism of fatty acids, plays a central role in ferroptosis. In order for the lethal mechanism to be triggered, a certain amount of specific oxidized lipid molecules must be present in membranes. “Acsl4 is critically involved in shaping the cellular lipid composition by storing more poly-unsaturated long-chain fatty acids in cellular membranes, thereby providing the starting materials for the generation of the lethal lipid signals driving ferroptosis” explains PhD student Sebastian Doll, first author of one of the two studies. “Previously it was assumed that iron-dependent lipid oxidation occurs randomly; however, our data now demonstrate that ACSL4 centrally contributes to the formation of oxidized lipid death signals in ferroptosis.”
Potential applications for the treatment of cancer and neurodegenerative diseases
Although the term ‘cell death’ is generally viewed as an adverse event and thus has a rather negative image, it has been shown – particularly in the context of cancer – that the selective destruction of aberrant cells is vital for the human body. The scientists therefore examined the role of ACSL4 in this context. They showed that a subset of breast cancer cells (i.e. triple negative breast cancer cells) that do not produce ACSL4 are extremely resistant to ferroptosis, while those that express the enzyme respond very sensitively to ferroptosis induction. “This is a highly interesting finding given the fact that the presence of ACSL4 determines whether or not cells can embark on the ferroptosis pathway” explains Dr. José Pedro Friedmann Angeli, who was centrally involved in both studies. It is thus well conceivable, he says, that the molecule could be used as a biomarker in cancer patient stratification.
The researchers also provided the first molecular approach for targeting ACSL4 in the signalling pathway. In a model experiment using thiazolidinediones, a class of active compounds commonly used in the treatment of diabetes, they succeeded in slowing down the process of ferroptosis.
“Our intriguing insights that the ACSL4 enzyme plays a substantial role in the process of cell death provide novel cues for yet-unrecognized therapeutic approaches towards inhibiting ferroptosis in degenerative diseases or inducing ferroptosis in certain tumor diseases,” says study leader Dr. Conrad. In particular, tumors that are otherwise very difficult to treat with standard chemotherapy might be amenable for ferroptosis therapy, the researchers say.
Background: Up until now ferroptosis is only partially understood. However, the importance of cellular suicide has already been impressively documented by research concerning apoptosis, the first identified cell death pathway, which has been explored by far more comprehensively throughout the last decades than ferroptosis. Moreover, ferroptosis appears to play a key role in cancer and in cell demise in response to oxidative stress (e.g. in neurons). Previously, only a few essential molecules, such as glutathione peroxidase 4 (GPX4), have been implicated in the ferroptotic process.
Source: Marcus Conrad – Helmholtz Zentrum München
Image Source: This NeuroscienceNews.com image is credited to Helmholtz Zentrum München.
Original Research: Abstract for “ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition” by Sebastian Doll, Bettina Proneth, Yulia Y Tyurina, Elena Panzilius, Sho Kobayashi, Irina Ingold, Martin Irmler, Johannes Beckers, Michaela Aichler, Axel Walch, Holger Prokisch, Dietrich Trümbach, Gaowei Mao, Feng Qu, Hulya Bayir, Joachim Füllekrug, Christina H Scheel, Wolfgang Wurst, Joel A Schick, Valerian E Kagan, José Pedro Friedmann Angeli & Marcus Conrad in Nature Chemical Biology. Published online November 14 2016 doi:10.1038/nchembio.2239
Abstract for “Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis” by Valerian E Kagan, Gaowei Mao, Feng Qu, Jose Pedro Friedmann Angeli, Sebastian Doll, Claudette St Croix, Haider Hussain Dar, Bing Liu, Vladimir A Tyurin, Vladimir B Ritov, Alexandr A Kapralov, Andrew A Amoscato, Jianfei Jiang, Tamil Anthonymuthu, Dariush Mohammadyani, Qin Yang, Bettina Proneth, Judith Klein-Seetharaman, Simon Watkins, Ivet Bahar, Joel Greenberger, Rama K Mallampalli, Brent R Stockwell, Yulia Y Tyurina, Marcus Conrad & Hülya Bayır in Nature Chemical Biology. Published online November 14 2016 doi:10.1038/nchembio.2238
[cbtabs][cbtab title=”MLA”]Helmholtz Zentrum München. “How Cells Die in Ferroptosis.” NeuroscienceNews. NeuroscienceNews, 16 November 2016.
<https://neurosciencenews.com/ferroptosis-cell-death-5532/>.[/cbtab][cbtab title=”APA”]Helmholtz Zentrum München. (2016, November 16). How Cells Die in Ferroptosis. NeuroscienceNews. Retrieved November 16, 2016 from https://neurosciencenews.com/ferroptosis-cell-death-5532/[/cbtab][cbtab title=”Chicago”]Helmholtz Zentrum München. “How Cells Die in Ferroptosis.” https://neurosciencenews.com/ferroptosis-cell-death-5532/ (accessed November 16, 2016).[/cbtab][/cbtabs]
Abstract
ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition
Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches—a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines—to 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. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
“ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition” by Sebastian Doll, Bettina Proneth, Yulia Y Tyurina, Elena Panzilius, Sho Kobayashi, Irina Ingold, Martin Irmler, Johannes Beckers, Michaela Aichler, Axel Walch, Holger Prokisch, Dietrich Trümbach, Gaowei Mao, Feng Qu, Hulya Bayir, Joachim Füllekrug, Christina H Scheel, Wolfgang Wurst, Joel A Schick, Valerian E Kagan, José Pedro Friedmann Angeli & Marcus Conrad in Nature Chemical Biology. Published online November 14 2016 doi:10.1038/nchembio.2239
Abstract
Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis
Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis—a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered 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. This oxidative PE death pathway may also represent a target for drug discovery.
“Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis” by Valerian E Kagan, Gaowei Mao, Feng Qu, Jose Pedro Friedmann Angeli, Sebastian Doll, Claudette St Croix, Haider Hussain Dar, Bing Liu, Vladimir A Tyurin, Vladimir B Ritov, Alexandr A Kapralov, Andrew A Amoscato, Jianfei Jiang, Tamil Anthonymuthu, Dariush Mohammadyani, Qin Yang, Bettina Proneth, Judith Klein-Seetharaman, Simon Watkins, Ivet Bahar, Joel Greenberger, Rama K Mallampalli, Brent R Stockwell, Yulia Y Tyurina, Marcus Conrad & Hülya Bayır in Nature Chemical Biology. Published online November 14 2016 doi:10.1038/nchembio.2238
