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. [2] The ionic imbalance that occurs subsequently causes the cell to swell without a concurrent change in membrane permeability to reverse the swelling. [3] 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. [4] The final stage is cell death and removal of the cell via phagocytosis mediated by an inflammatory response. [5]

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. [6]

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. [7] The phagocytic disposal of apoptotic cells prevents the release of cellular debris that could induce an inflammatory response in neighboring cells. [8] 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. [9] Additionally, apoptosis and the degradation of intracellular organelles is mediated by caspase activation, particularly caspase-3. [10] Oligonuclosomal DNA fragmentation is initiated by caspase-activated deoxyribonuclease following caspase-3 mediated cleavage of the enzyme’s inhibitor, ICAD. [11] In contrast, the oncotic pathway has been shown to be caspase-3 independent. [12]

The primary determinant of cell death occurring via the oncotic or apoptotic pathway is cellular ATP levels. [13] Apoptosis is contingent upon ATP levels to form the energy dependent apoptosome. [14] A distinct biochemical event only seen in oncosis is the rapid depletion of intracellular ATP. [15] The lack of intracellular ATP results in a deactivation of sodium and potassium ATPase within the compromised cell membrane. [16] 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. [17] 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. [18] 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. [19]

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms. 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 between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, approximately twenty to thirty billion cells die per day.

<span class="mw-page-title-main">Necrosis</span> Unprogrammed cell death caused by external cell injury

Necrosis is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death. While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal.

<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.

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

Fas ligand is a type-II transmembrane protein expressed on cytotoxic T lymphocytes. Its binding with Fas receptor (FasR) induces programmed cell death in the FasR-carrying target cell. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.

<span class="mw-page-title-main">Apoptosome</span>

The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal (intrinsic) or external (extrinsic) cell death stimulus. Stimuli can vary from DNA damage and viral infection to developmental cues such as those leading to the degradation of a tadpole's tail.

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">Bcl-2-associated X protein</span> Mammalian protein found in Homo sapiens

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span>

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">HSPA1A</span>

Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the HSPA1A gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. In addition, Hsp72 also facilitates DNA repair. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and inflammatory diseases such as Diabetes mellitus type 2 and rheumatoid arthritis.

<span class="mw-page-title-main">Bcl-2-like protein 1</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 1 is a protein encoded in humans by the BCL2L1 gene. Through alternative splicing, the gene encodes both of the human proteins Bcl-xL and Bcl-xS.

<span class="mw-page-title-main">RIPK1</span>

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis and necroptosis. Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK.

<span class="mw-page-title-main">HSPA1L</span>

Heat shock 70 kDa protein 1L is a protein that in humans is encoded by the HSPA1L gene on chromosome 6. As a member of the heat shock protein 70 (Hsp70) family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and Graft-versus-host disease.

<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.

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. Currently in Phase I clinical trials, it is believed to be safe to co-administer with cisplatin.

<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.

<span class="mw-page-title-main">ADP/ATP translocase 2</span> Protein-coding gene in the species Homo sapiens

ADP/ATP translocase 2 is a protein that in humans is encoded by the SLC25A5 gene on the X chromosome.

<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.

<span class="mw-page-title-main">FAM162A</span>

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. ↑ Weerasinghe, Priya, and L. Maximilian Buja. "Oncosis: an important non-apoptotic mode of cell death." Experimental and molecular pathology 93.3 (2012): 302-308.
  2. ↑ Weerasinghe, Priya, and L. Maximilian Buja. "Oncosis: an important non-apoptotic mode of cell death." Experimental and molecular pathology 93.3 (2012): 302-308.
  3. ↑ Weerasinghe, Priya, and L. Maximilian Buja. "Oncosis: an important non-apoptotic mode of cell death." Experimental and molecular pathology 93.3 (2012): 302-308.
  4. ↑ Weerasinghe, Priya, and L. Maximilian Buja. "Oncosis: an important non-apoptotic mode of cell death." Experimental and molecular pathology 93.3 (2012): 302-308.
  5. ↑ Scarabelli, T. M., Knight, R., Stephanou, A., Townsend, P., Chen-Scarabelli, 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.
  6. ↑ 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.
  7. ↑ Majno, G., & Joris, I. (1995). Apoptosis, oncosis, and necrosis. An overview of cell death. The American journal of pathology, 146(1), 3.
  8. ↑ Ren, Y., & Savill, J. (1998). Apoptosis: the importance of being eaten. Cell Death & Differentiation, 5(7), 563-568.
  9. ↑ Ren, Y., & Savill, J. (1998). Apoptosis: the importance of being eaten. Cell Death & Differentiation, 5(7), 563-568.
  10. ↑ Earnshaw, W. C., Martins, L. M., & Kaufmann, S. H. (1999). Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annual review of biochemistry, 68(1), 383-424.
  11. ↑ Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A., & Nagata, S. (1998). A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature, 391(6662), 43-50.
  12. ↑ Weerasinghe, Priya, and L. Maximilian Buja. "Oncosis: an important non-apoptotic mode of cell death." Experimental and molecular pathology 93.3 (2012): 302-308.
  13. ↑ Eguchi Y, Shimizu S and Tsujimoto Y (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res. in press
  14. ↑ Eguchi Y, Shimizu S and Tsujimoto Y (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res. in press
  15. ↑ Eguchi Y, Shimizu S and Tsujimoto Y (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res. in press
  16. ↑ Yamamoto, N., Smith, M. W., Maki, A., Berezesky, I. K., & Trump, B. F. (1994). Role of cytosolic Ca2+ and protein kinases in the induction of the hsp70 gene. Kidney International, 45(4), 1093-1104.
  17. ↑ Yamamoto, N., Smith, M. W., Maki, A., Berezesky, I. K., & Trump, B. F. (1994). Role of cytosolic Ca2+ and protein kinases in the induction of the hsp70 gene. Kidney International, 45(4), 1093-1104.
  18. ↑ Mills, E. M., Xu, D., Fergusson, M. M., Combs, C. A., Xu, Y., & Finkel, T. (2002). Regulation of cellular oncosis by uncoupling protein 2. Journal of Biological Chemistry, 277(30), 27385-27392.
  19. ↑ Mills, E. M., Xu, D., Fergusson, M. M., Combs, C. A., Xu, Y., & Finkel, T. (2002). Regulation of cellular oncosis by uncoupling protein 2. Journal of Biological Chemistry, 277(30), 27385-27392.
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