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Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure

Ferroptosis is a recently recognized caspase-independent form of regulated cell death that is characterized by the accumulation of lethal lipid ROS produced through iron-dependent lipid peroxidation. Considering that regulation of fatty acid metabolism is responsible for the membrane-resident pool o...

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Autores principales: Müller, Tammo, Dewitz, Christin, Schmitz, Jessica, Schröder, Anna Sophia, Bräsen, Jan Hinrich, Stockwell, Brent R., Murphy, James M., Kunzendorf, Ulrich, Krautwald, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589788/
https://www.ncbi.nlm.nih.gov/pubmed/28551825
http://dx.doi.org/10.1007/s00018-017-2547-4
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author Müller, Tammo
Dewitz, Christin
Schmitz, Jessica
Schröder, Anna Sophia
Bräsen, Jan Hinrich
Stockwell, Brent R.
Murphy, James M.
Kunzendorf, Ulrich
Krautwald, Stefan
author_facet Müller, Tammo
Dewitz, Christin
Schmitz, Jessica
Schröder, Anna Sophia
Bräsen, Jan Hinrich
Stockwell, Brent R.
Murphy, James M.
Kunzendorf, Ulrich
Krautwald, Stefan
author_sort Müller, Tammo
collection PubMed
description Ferroptosis is a recently recognized caspase-independent form of regulated cell death that is characterized by the accumulation of lethal lipid ROS produced through iron-dependent lipid peroxidation. Considering that regulation of fatty acid metabolism is responsible for the membrane-resident pool of oxidizable fatty acids that undergo lipid peroxidation in ferroptotic processes, we examined the contribution of the key fatty acid metabolism enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), in regulating ferroptosis. By using CRISPR/Cas9 technology, we found that knockout of Acsl4 in ferroptosis-sensitive murine and human cells conferred protection from erastin- and RSL3-induced cell death. In the same cell types, deletion of mixed lineage kinase domain-like (Mlkl) blocked susceptibility to necroptosis, as expected. Surprisingly, these studies also revealed ferroptosis and necroptosis are alternative, in that resistance to one pathway sensitized cells to death via the other pathway. These data suggest a mechanism by which one regulated necrosis pathway compensates for another when either ferroptosis or necroptosis is compromised. We verified the synergistic contributions of ferroptosis and necroptosis to tissue damage during acute organ failure in vivo. Interestingly, in the course of pathophysiological acute ischemic kidney injury, ACSL4 was initially upregulated and its expression level correlated with the severity of tissue damage. Together, our findings reveal ACSL4 to be a reliable biomarker of the emerging cell death modality of ferroptosis, which may also serve as a novel therapeutic target in preventing pathological cell death processes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00018-017-2547-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-55897882017-09-22 Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure Müller, Tammo Dewitz, Christin Schmitz, Jessica Schröder, Anna Sophia Bräsen, Jan Hinrich Stockwell, Brent R. Murphy, James M. Kunzendorf, Ulrich Krautwald, Stefan Cell Mol Life Sci Original Aritcle Ferroptosis is a recently recognized caspase-independent form of regulated cell death that is characterized by the accumulation of lethal lipid ROS produced through iron-dependent lipid peroxidation. Considering that regulation of fatty acid metabolism is responsible for the membrane-resident pool of oxidizable fatty acids that undergo lipid peroxidation in ferroptotic processes, we examined the contribution of the key fatty acid metabolism enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), in regulating ferroptosis. By using CRISPR/Cas9 technology, we found that knockout of Acsl4 in ferroptosis-sensitive murine and human cells conferred protection from erastin- and RSL3-induced cell death. In the same cell types, deletion of mixed lineage kinase domain-like (Mlkl) blocked susceptibility to necroptosis, as expected. Surprisingly, these studies also revealed ferroptosis and necroptosis are alternative, in that resistance to one pathway sensitized cells to death via the other pathway. These data suggest a mechanism by which one regulated necrosis pathway compensates for another when either ferroptosis or necroptosis is compromised. We verified the synergistic contributions of ferroptosis and necroptosis to tissue damage during acute organ failure in vivo. Interestingly, in the course of pathophysiological acute ischemic kidney injury, ACSL4 was initially upregulated and its expression level correlated with the severity of tissue damage. Together, our findings reveal ACSL4 to be a reliable biomarker of the emerging cell death modality of ferroptosis, which may also serve as a novel therapeutic target in preventing pathological cell death processes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00018-017-2547-4) contains supplementary material, which is available to authorized users. Springer International Publishing 2017-05-27 2017 /pmc/articles/PMC5589788/ /pubmed/28551825 http://dx.doi.org/10.1007/s00018-017-2547-4 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Aritcle
Müller, Tammo
Dewitz, Christin
Schmitz, Jessica
Schröder, Anna Sophia
Bräsen, Jan Hinrich
Stockwell, Brent R.
Murphy, James M.
Kunzendorf, Ulrich
Krautwald, Stefan
Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure
title Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure
title_full Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure
title_fullStr Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure
title_full_unstemmed Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure
title_short Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure
title_sort necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure
topic Original Aritcle
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589788/
https://www.ncbi.nlm.nih.gov/pubmed/28551825
http://dx.doi.org/10.1007/s00018-017-2547-4
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