loading...| Preferred Name | Necrosis | |
| Synonyms |
PathwayType: signaling Organ: generic Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-cf1c902d-95d3-4b51-93b9-b4137ca8e05a Organ_System: generic Tissue: generic Notes: Headnote: Necrotic cell death is characterized by cytoplasmic and organelle swelling, followed by the loss of cell membrane integrity and the release of the cellular contents into the surrounding extracellular space. This usually occurs under conditions of extreme damage such as ischemia or trauma when apoptosis fails to occur. Signaling description: An important consequence of necrotic cell death is the loss of plasma membrane integrity, thereby allowing the escape of intracellular material from the cell. Mechanical damage of membranes leads to the release of free radicals of hydrogen, oxygen, and others. Superoxide radical is the major initial free radical species, which can be converted into other reactive species. In the mitochondria, superoxide radical is generated by the capture of electrons in the mitochondrial electron transport chain escaping from the electron transport chain by molecular oxygen (O2). Superoxide can be rapidly converted to hydrogen peroxide (H2O2) by superoxide dismutases (SOD1), which can be reused to generate superoxide radicals. H2O2 diffuses freely across cellular membranes and can interact with iron (Fe2+) in the Fenton reaction in the lysosomes since they are rich in free Fe2+ and lack H2O2-detoxifying enzymes. In the presence of transition metals such as Fe2+, H2O2 can be converted into hydroxyl radicals that are highly reactive and can cause damage to lipids, proteins, and DNA. Nitric oxide (NO) is a reactive radical produced from arginine by nitric oxide synthase (NOS). NO has a very short half-life and can react with superoxide to form peroxynitrite. Outcome effects: The targets of ROS are proteins and the polyunsaturated fatty acid residues in the membrane phospholipids which are extremely sensitive to oxidation. Free radicals lead to lipid peroxidation and the destruction of cellular membranes. Oxidative stress directly leads to damage of cellular macromolecules including DNA, proteins, and lipids. Furthermore, extensive DNA damage during necrosis causes hyperactivation of PARP1 and leads to necrotic cell death. When DNA damage is moderate, PARP1 participates in DNA repair processes. However, excessive PARP1 activation is involved in catalyzing the hydrolysis of NAD into nicotinamide and poly(ADPribose) (PAR) which leads to ATP depletion, irreversible cellular energy failure, and necrotic cell death. PARP1-mediated cell death requires the activation of RIPK1 and TRAF2. Necrosis can be classified as either stochastic or programmed (necroptosis). Necroptosis has now been established as a regulated necrotic cell death pathway controlled by TNF, RIPK1 and RIPK3 kinases. Necrosis causes lipid peroxidation of intracellular membranes of endoplasmic reticulum, lysosomes, and mitochondria and leads to the release of calcium (Ca2+) and proteolytic enzymes into the cytoplasm where they further digest cellular content and expose it to extracellular space. The molecules that are released after necrotic cell death and may cause inflammation are called damage-associated molecular patterns (DAMPs). There are also extracellular DAMPs which are released after the degradation of extracellular matrix caused by injury. For example, fragments of hyaluronan, heparin sulfate, and biglycan are generated as a result of proteolysis catalyzed either by enzymes released from dying cells or by proteases activated to promote tissue repair and remodeling. Highlighted proteins: Entities with elevated level are highlighted in red, and entities with reduced level are highlighted in blue. NodeType: Pathway Description: Necrotic cell death is characterized by cytoplasmic and organelle swelling, followed by the loss of cell membrane integrity and the release of the cellular contents into extracellular space. Pathway is built manually using published studies. Source: Cell Process CellType: generic |
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| ID |
urn:agi-pathway:uuid-cf1c902d-95d3-4b51-93b9-b4137ca8e05a |
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| database_cross_reference |
PS:PathwayType PS:Description PS:Tissue PS:Pathway_Author PS:Link PS:CellType PS:Organ_System PS:NodeType PS:Notes PS:Organ PS:Source |
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| has_exact_synonym |
PathwayType: signaling Organ: generic Pathway_Author: A. Nesterova ORCID:0000-0002-9448-8101 Organ_System: generic Tissue: generic Notes: Headnote: Necrotic cell death is characterized by cytoplasmic and organelle swelling, followed by the loss of cell membrane integrity and the release of the cellular contents into the surrounding extracellular space. This usually occurs under conditions of extreme damage such as ischemia or trauma when apoptosis fails to occur. Signaling description: An important consequence of necrotic cell death is the loss of plasma membrane integrity, thereby allowing the escape of intracellular material from the cell. Mechanical damage of membranes leads to the release of free radicals of hydrogen, oxygen, and others. Superoxide radical is the major initial free radical species, which can be converted into other reactive species. In the mitochondria, superoxide radical is generated by the capture of electrons in the mitochondrial electron transport chain escaping from the electron transport chain by molecular oxygen (O2). Superoxide can be rapidly converted to hydrogen peroxide (H2O2) by superoxide dismutases (SOD1), which can be reused to generate superoxide radicals. H2O2 diffuses freely across cellular membranes and can interact with iron (Fe2+) in the Fenton reaction in the lysosomes since they are rich in free Fe2+ and lack H2O2-detoxifying enzymes. In the presence of transition metals such as Fe2+, H2O2 can be converted into hydroxyl radicals that are highly reactive and can cause damage to lipids, proteins, and DNA. Nitric oxide (NO) is a reactive radical produced from arginine by nitric oxide synthase (NOS). NO has a very short half-life and can react with superoxide to form peroxynitrite. Outcome effects: The targets of ROS are proteins and the polyunsaturated fatty acid residues in the membrane phospholipids which are extremely sensitive to oxidation. Free radicals lead to lipid peroxidation and the destruction of cellular membranes. Oxidative stress directly leads to damage of cellular macromolecules including DNA, proteins, and lipids. Furthermore, extensive DNA damage during necrosis causes hyperactivation of PARP1 and leads to necrotic cell death. When DNA damage is moderate, PARP1 participates in DNA repair processes. However, excessive PARP1 activation is involved in catalyzing the hydrolysis of NAD into nicotinamide and poly(ADPribose) (PAR) which leads to ATP depletion, irreversible cellular energy failure, and necrotic cell death. PARP1-mediated cell death requires the activation of RIPK1 and TRAF2. Necrosis can be classified as either stochastic or programmed (necroptosis). Necroptosis has now been established as a regulated necrotic cell death pathway controlled by TNF, RIPK1 and RIPK3 kinases. Necrosis causes lipid peroxidation of intracellular membranes of endoplasmic reticulum, lysosomes, and mitochondria and leads to the release of calcium (Ca2+) and proteolytic enzymes into the cytoplasm where they further digest cellular content and expose it to extracellular space. The molecules that are released after necrotic cell death and may cause inflammation are called damage-associated molecular patterns (DAMPs). There are also extracellular DAMPs which are released after the degradation of extracellular matrix caused by injury. For example, fragments of hyaluronan, heparin sulfate, and biglycan are generated as a result of proteolysis catalyzed either by enzymes released from dying cells or by proteases activated to promote tissue repair and remodeling. Highlighted proteins: Entities with elevated level are highlighted in red, and entities with reduced level are highlighted in blue. NodeType: Pathway Description: Necrotic cell death is characterized by cytoplasmic and organelle swelling, followed by the loss of cell membrane integrity and the release of the cellular contents into extracellular space. Pathway is built manually using published studies. Source: Cell Process CellType: generic |
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| id |
urn:agi-pathway:uuid-cf1c902d-95d3-4b51-93b9-b4137ca8e05a |
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| label |
Necrosis |
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| notation |
uuid-cf1c902d-95d3-4b51-93b9-b4137ca8e05a |
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| prefLabel |
Necrosis |
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| treeView |
urn:agi-folder:inflammation_initiation urn:agi-folder:apoptosis_and_cell_death urn:agi-folder:generic urn:agi-folder:n |
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| subClassOf |
urn:agi-folder:inflammation_initiation urn:agi-folder:apoptosis_and_cell_death urn:agi-folder:generic urn:agi-folder:n |