Ischemic cell death

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Ischemic cell death, or oncosis, is a form of accidental cell death. The process is characterized by an ATP depletion within the cell leading to impairment of ionic pumps, cell swelling, clearing of the cytosol, dilation of the endoplasmic reticulum and golgi apparatus, mitochondrial condensation, chromatin clumping, and cytoplasmic bleb formation. [1] Oncosis refers to a series of cellular reactions following injury that precedes cell death. The process of oncosis is divided into three stages. First, the cell becomes committed to oncosis as a result of damage incurred to the plasma membrane through toxicity or ischemia, resulting in the leak of ions and water due to ATP depletion. [1] The ionic imbalance that occurs subsequently causes the cell to swell without a concurrent change in membrane permeability to reverse the swelling. [1] In stage two, the reversibility threshold for the cell is passed and the cell becomes committed to cell death. During this stage the membrane becomes abnormally permeable to trypan blue and propidium iodide, indicating membrane compromise. [1] The final stage is cell death and removal of the cell via phagocytosis mediated by an inflammatory response. [2]

Contents

Etymology

Although ischemic cell death is the accepted name of the process, the alternative name of oncosis was introduced as the process involves the affected cell(s) swelling to an abnormally large size in known models. This is thought to be caused by failure of the plasma membrane's ionic pumps. The name oncosis (derived from ónkos, meaning largeness, and ónkosis, meaning swelling) was first introduced in 1910 by pathologist Friedrich Daniel von Recklinghausen. [3]

Comparison to apoptosis

Oncosis and apoptosis are distinct processes of cellular death. Oncosis is characterized by cellular swelling caused by a failure in ion transporter function. Apoptosis, or programmed cell death involves a series of cell shrinking processes, beginning with cell size reduction and pyknosis, followed by cell budding and karyorrhexis, and phagocytosis by macrophages or neighboring cells due to size decrease. [3] The phagocytic disposal of apoptotic cells prevents the release of cellular debris that could induce an inflammatory response in neighboring cells. In opposition, the leakage of cellular content associated with membrane disruption in oncosis often incites an inflammatory response in neighboring tissue, causing further cellular injury. [3] Additionally, apoptosis and the degradation of intracellular organelles is mediated by caspase activation, particularly caspase-3. [4] Oligonuclosomal DNA fragmentation is initiated by caspase-activated deoxyribonuclease following caspase-3 mediated cleavage of the enzyme’s inhibitor, ICAD. [5] In contrast, the oncotic pathway has been shown to be caspase-3 independent. [1]

The primary determinant of cell death occurring via the oncotic or apoptotic pathway is cellular ATP levels. Apoptosis is contingent upon ATP levels to form the energy dependent apoptosome. A distinct biochemical event only seen in oncosis is the rapid depletion of intracellular ATP. [6] The lack of intracellular ATP results in a deactivation of sodium and potassium ATPase within the compromised cell membrane. The lack of ion transport at the cell membrane leads to an accumulation of sodium and chloride ions within the cell with a concurrent water influx, contributing to the hallmark cellular swelling of oncosis. [7] As with apoptosis, oncosis has been shown to be genetically programmed and dependent on expression levels of uncoupling protein-2 (UCP-2) in HeLa cells. An increase in UCP-2 levels leads to a rapid decrease in mitochondrial membrane potential, reducing mitochondrial NADH and intracellular ATP levels, initiating the oncotic pathway. The anti-apoptotic gene product Bcl-2 is not an active inhibitor of UCP-2 initiated cell death, further distinguishing oncosis and apoptosis as distinct cellular death mechanisms. [8]

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Form of programmed cell death

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<span class="mw-page-title-main">Karyorrhexis</span> Destructive fragmentation of the nucleus of a dying cell

Karyorrhexis is the destructive fragmentation of the nucleus of a dying cell whereby its chromatin is distributed irregularly throughout the cytoplasm. It is usually preceded by pyknosis and can occur as a result of either programmed cell death (apoptosis), cellular senescence, or necrosis.

<span class="mw-page-title-main">Cell death</span> Biological cell ceasing to carry out its functions

Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as diseases, localized injury, or the death of the organism of which the cells are part. Apoptosis or Type I cell-death, and autophagy or Type II cell-death are both forms of programmed cell death, while necrosis is a non-physiological process that occurs as a result of infection or injury.

The ischemic (ischaemic) cascade is a series of biochemical reactions that are initiated in the brain and other aerobic tissues after seconds to minutes of ischemia. This is typically secondary to stroke, injury, or cardiac arrest due to heart attack. Most ischemic neurons that die do so due to the activation of chemicals produced during and after ischemia. The ischemic cascade usually goes on for two to three hours but can last for days, even after normal blood flow returns.

Cell damage is a variety of changes of stress that a cell suffers due to external as well as internal environmental changes. Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. Cell damage can be reversible or irreversible. Depending on the extent of injury, the cellular response may be adaptive and where possible, homeostasis is restored. Cell death occurs when the severity of the injury exceeds the cell's ability to repair itself. Cell death is relative to both the length of exposure to a harmful stimulus and the severity of the damage caused. Cell death may occur by necrosis or apoptosis.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">ENDOG</span> Protein-coding gene in the species Homo sapiens

Endonuclease G, mitochondrial is an enzyme that in humans is encoded by the ENDOG gene. This protein primarily participates in caspase-independent apoptosis via DNA degradation when translocating from the mitochondrion to nucleus under oxidative stress. As a result, EndoG has been implicated in cancer, aging, and neurodegenerative diseases such as Parkinson's disease (PD). Regulation of its expression levels thus holds potential to treat or ameliorate those conditions.

<span class="mw-page-title-main">Apoptotic DNA fragmentation</span> Cleavage of DNA into tiny pieces during apoptosis

Apoptotic DNA fragmentation is a key feature of apoptosis, a type of programmed cell death. Apoptosis is characterized by the activation of endogenous endonucleases, particularly the caspase-3 activated DNase (CAD), with subsequent cleavage of nuclear DNA into internucleosomal fragments of roughly 180 base pairs (bp) and multiples thereof (360, 540 etc.). The apoptotic DNA fragmentation is being used as a marker of apoptosis and for identification of apoptotic cells either via the DNA laddering assay, the TUNEL assay, or the by detection of cells with fractional DNA content ("sub G1 cells") on DNA content frequency histograms e.g. as in the Nicoletti assay.

<span class="mw-page-title-main">ADP/ATP translocase 4</span> Protein-coding gene in the species Homo sapiens

ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4. This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential. In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival. Outside this role, the SLC25AC31 gene has not been implicated in any human disease.

Safingol is a lyso-sphingolipid protein kinase inhibitor. It has the molecular formula C18H39NO2 and is a colorless solid. Medicinally, safingol has demonstrated promising anticancer potential as a modulator of multi-drug resistance and as an inducer of necrosis. The administration of safingol alone has not been shown to exert a significant effect on tumor cell growth. However, preclinical and clinical studies have shown that combining safingol with conventional chemotherapy agents such as fenretinide, vinblastine, irinotecan and mitomycin C can dramatically potentiate their antitumor effects. In phase I clinical trials, it was found to be safe to co-administer with cisplatin, but caused reversible dose-dependent hepatotoxicity.

Pseudoapoptosis can be defined from multiple viewpoints, with an underlying premise of the differences in cellular processes and states relating to apoptosis. Pseudoapoptosis can be referred to as an apoptotic-like cellular state that can be readily reversed, or as a process that induces rapid apoptosis through the introduction of drugs such as bleomycin.

<span class="mw-page-title-main">Necroptosis</span> Programmed form of necrosis, or inflammatory cell death

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

Anoxic depolarization is a progressive and uncontrollable depolarization of neurons during stroke or brain ischemia in which there is an inadequate supply of blood to the brain. Anoxic depolarization is induced by the loss of neuronal selective membrane permeability and the ion gradients across the membrane that are needed to support neuronal activity. Normally, the Na+/K+-ATPase pump maintains the transmembrane gradients of K+ and Na+ ions, but with anoxic brain injury, the supply of energy to drive this pump is lost. The hallmarks of anoxic depolarization are increased concentrations of extracellular K+ ions, intracellular Na+ and Ca2+ ions, and extracellular glutamate and aspartate. Glutamate and aspartate are normally present as the brain's primary excitatory neurotransmitters, but high concentrations activate a number of downstream apoptotic and necrotic pathways. This results in neuronal dysfunction and brain death.

<span class="mw-page-title-main">Paraptosis</span> Type of programmed cell death distinct from apoptosis and necrosis

Paraptosis is a type of programmed cell death, morphologically distinct from apoptosis and necrosis. The defining features of paraptosis are cytoplasmic vacuolation, independent of caspase activation and inhibition, and lack of apoptotic morphology. Paraptosis lacks several of the hallmark characteristics of apoptosis, such as membrane blebbing, chromatin condensation, and nuclear fragmentation. Like apoptosis and other types of programmed cell death, the cell is involved in causing its own death, and gene expression is required. This is in contrast to necrosis, which is non-programmed cell death that results from injury to the cell.

Diallyl trisulfide (DATS), also known as Allitridin, is an organosulfur compound with the formula S(SCH2CH=CH2)2. It is one of several compounds produced by hydrolysis of allicin, including diallyl disulfide and diallyl tetrasulfide; DATS is one of the most potent.

<span class="mw-page-title-main">FASTKD2</span> Protein-coding gene in the species Homo sapiens

FAST kinase domain-containing protein 2 (FASTKD2) is a protein that in humans is encoded by the FASTKD2 gene on chromosome 2. This protein is part of the FASTKD family, which is known for regulating the energy balance of mitochondria under stress. FASTKD2 has been implicated in mitochondrial encephalomyopathy, breast cancer, and prostate cancer.

<span class="mw-page-title-main">FAM162A</span> Protein-coding gene in the species Homo sapiens

Human growth and transformation-dependent protein (HGTD-P), also called E2-induced gene 5 protein (E2IG5), is a protein that in humans is encoded by the FAM162A gene on chromosome 3. This protein promotes intrinsic apoptosis in response to hypoxia via interactions with hypoxia-inducible factor-1α (HIF-1α). As a result, it has been associated with cerebral ischemia, myocardial infarction, and various cancers.

References

  1. 1 2 3 4 5 Weerasinghe, Priya; Buja, L. Maximilian (2012). "Oncosis: An important non-apoptotic mode of cell death". Experimental and Molecular Pathology. 93 (3): 302–308. doi:10.1016/j.yexmp.2012.09.018. PMID   23036471.
  2. ↑ Scarabelli, T.; Knight, R.; Stephanou, A.; Townsend, P.; Chenscarabelli, C.; Lawrence, K.; Gottlieb, R.; Latchman, D.; Narula, J. (2006). "Clinical Implications of Apoptosis in Ischemic Myocardium". Current Problems in Cardiology. 31 (3): 181–264. doi:10.1016/j.cpcardiol.2005.11.002. PMID   16503249.
  3. 1 2 3 Majno; Joris (1995). "Apoptosis, oncosis, and necrosis. An overview of cell death". Am. J. Pathol. 146 (1): 1–2, 16–19. PMC   1870771 . PMID   7856735.
  4. ↑ Earnshaw, William C.; Martins, Luis M.; Kaufmann, Scott H. (1999). "Mammalian Caspases: Structure, Activation, Substrates, and Functions During Apoptosis". Annual Review of Biochemistry. 68: 383–424. doi:10.1146/annurev.biochem.68.1.383. PMID   10872455.
  5. ↑ Enari, Masato; Sakahira, Hideki; Yokoyama, Hideki; Okawa, Katsuya; Iwamatsu, Akihiro; Nagata, Shigekazu (1998). "A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD". Nature. 391 (6662): 43–50. doi:10.1038/34112. PMID   9422506.
  6. ↑ Eguchi, Y.; Shimizu, S.; Tsujimoto, Y. (1997). "Intracellular ATP levels determine cell death fate by apoptosis or necrosis". Cancer Research. 57 (10): 1835–1840. PMID   9157970.
  7. ↑ Yamamoto, Naritaka; Smith, Mary W.; Maki, Atsuhiko; Berezesky, Irene K.; Trump, Benjamin F. (1994). "Role of cytosolic Ca2+ and protein kinases in the induction of the hsp70 gene". Kidney International. 45 (4): 1093–1104. doi:10.1038/ki.1994.146. PMID   8007579.
  8. ↑ Mills, Edward M.; Xu, Dong; Fergusson, Marı́a M.; Combs, Christian A.; Xu, Yuhui; Finkel, Toren (2002). "Regulation of Cellular Oncosis by Uncoupling Protein 2". Journal of Biological Chemistry. 277 (30): 27385–27392. doi: 10.1074/jbc.M111860200 . PMID   12011039.
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