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Cell death in health and disease.

Lockshin RA, Zakeri Z - J. Cell. Mol. Med. (2007)

Bottom Line: Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely-associated and interacting proteins.Another complicating factor is that many death-associated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them.In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, St. John's University, Queens, NY 11439, USA. lockshin@stjohns.edu

ABSTRACT
Cell death is clearly an important factor in development, homeostasis, pathology, and in aging, but medical efforts based on controlling cell death have not become major aspects of medicine. There are several reasons why hopes have been slow to be fulfilled, and they present indications for new directions in research. Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely-associated and interacting proteins. But cells have many options other than apoptosis. These include autophagy, necrosis, atrophy, and stepwise or other alternate means of self-disassembly. The response of a cell to a noxious or otherwise intimidating signal will depend heavily on the history, lineage, and current status of the cell. Many metabolic and other processes adjust the sensitivity of cells to signals, and viruses aggressively attempt to regulate the death of their host cells. Another complicating factor is that many death-associated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them. In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion.

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Related in: MedlinePlus

The very late appearance of characteristics of apoptosis in metamorphosing insect cells. Upper row: appearance of lysosomes during the involution of the salivary gland of Drosophila, which in our hands has completely collapsed by 13 hrs after the beginning of puparium formation. Monodansylcadaverine detects no resolvable organelles prior to onset of metamorphosis, but by 6 hrs there are numerous perinuclear autophagic vacuoles (arrows) and by 9 hrs the vacuoles fill the cytoplasm (three figures on left). Lysotracker red ® detects modest activity by 9 hrs and large autophagic vacuoles by 12 hrs. Middle row: By 3 hrs into metamorphosis, the fine filamentous actin network, detected by rhodamine phalloidin, has given way to fine granular clumps of actin, which become more pronounced by 9 hrs. By 10 hrs the actin is in vacuoles that appear to be lysosomes, or clustered near the cell membranes. Lower row: Evidence for apoptosis occurs only very late. Both exteriorization of phosphatidylserine as detected by annexin V (left two panels) and appearance of TUNEL-positive nuclei (right two panels) occur after the 11th hr.We also confirmed the presence of caspase-positive granules at 12 hrs but, failing an interpretation of the significance of the granules, we withhold an interpretation. From doctoral research of Farhan S. Khan.
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fig01: The very late appearance of characteristics of apoptosis in metamorphosing insect cells. Upper row: appearance of lysosomes during the involution of the salivary gland of Drosophila, which in our hands has completely collapsed by 13 hrs after the beginning of puparium formation. Monodansylcadaverine detects no resolvable organelles prior to onset of metamorphosis, but by 6 hrs there are numerous perinuclear autophagic vacuoles (arrows) and by 9 hrs the vacuoles fill the cytoplasm (three figures on left). Lysotracker red ® detects modest activity by 9 hrs and large autophagic vacuoles by 12 hrs. Middle row: By 3 hrs into metamorphosis, the fine filamentous actin network, detected by rhodamine phalloidin, has given way to fine granular clumps of actin, which become more pronounced by 9 hrs. By 10 hrs the actin is in vacuoles that appear to be lysosomes, or clustered near the cell membranes. Lower row: Evidence for apoptosis occurs only very late. Both exteriorization of phosphatidylserine as detected by annexin V (left two panels) and appearance of TUNEL-positive nuclei (right two panels) occur after the 11th hr.We also confirmed the presence of caspase-positive granules at 12 hrs but, failing an interpretation of the significance of the granules, we withhold an interpretation. From doctoral research of Farhan S. Khan.

Mentions: There are many alternative paths. Typically, a large, cytoplasm-rich, post-mitotic or poorly mitotic cell such as a mammary epithelial cell has a big problem eliminating its cytoplasm, whereas a small, short-lived, highly mitotic cell subject to many mutagenic situations is more threatening because of its potentially damaged or mutated DNA. Thus apoptosis, with its rapid and complete destruction of DNA, is easily and promptly activated in cells of haematopoietic lineage, while mammary epithelial cells and others undertake massive autophagy. In insects, during metamorphosis the bulk of the larval tissue is destroyed, and cell death is easily timed and is tolerably synchronous. Here, apoptosis is an inconspicuous aspect of the cell death. During metamorphosis, the first 90% of the period during which the cell is dying is occupied by autophagic processes, with no activation of caspases, margination of chromatin, fragmentation of DNA or exteriorization of phosphatidyl serine. At the very end, when almost all cytoplasm has been consumed, one encounters evidence of apoptosis: condensation and margination of chromatin, fragmentation of DNA into nucleosome ladders, exteriorization of phosphatidyl serine and (though insect caspases differ from mammalian caspases and are harder to document) apparent activation of a caspase (Fig. 1). This is what we and others have called autophagic cell death, but it appears today in a different light. Although in the metamorphosing insect nutritional supplies are good (the adult or imaginal tissues are growing rapidly) the larval tissues do not thrive and undergo a type of autophagy that is normally associated with starving cells, cells deprived of trophic hormones or cells that have suffered substantial damage to organelles. It appears that, as in the case in many laboratory experiments, the cell dies only when autophagy fails to sustain it beyond a point of no return. In PC-12 cells deprived of nerve growth factor, the point of no return is the autophagic destruction of all their mitochondria. We do not know the limitation of the larval insect cells. Their tracheae (insect direct-to-cell breathing tubes) collapse and mitochondria are subjected to autophagy, suggesting an energy limitation, but they retain sufficient ATP ultimately to undergo apoptosis. We have no knowledge of the status of hormone receptors or translocators. The suggestion is that the autophagy is a survival mechanism carried beyond its limits.


Cell death in health and disease.

Lockshin RA, Zakeri Z - J. Cell. Mol. Med. (2007)

The very late appearance of characteristics of apoptosis in metamorphosing insect cells. Upper row: appearance of lysosomes during the involution of the salivary gland of Drosophila, which in our hands has completely collapsed by 13 hrs after the beginning of puparium formation. Monodansylcadaverine detects no resolvable organelles prior to onset of metamorphosis, but by 6 hrs there are numerous perinuclear autophagic vacuoles (arrows) and by 9 hrs the vacuoles fill the cytoplasm (three figures on left). Lysotracker red ® detects modest activity by 9 hrs and large autophagic vacuoles by 12 hrs. Middle row: By 3 hrs into metamorphosis, the fine filamentous actin network, detected by rhodamine phalloidin, has given way to fine granular clumps of actin, which become more pronounced by 9 hrs. By 10 hrs the actin is in vacuoles that appear to be lysosomes, or clustered near the cell membranes. Lower row: Evidence for apoptosis occurs only very late. Both exteriorization of phosphatidylserine as detected by annexin V (left two panels) and appearance of TUNEL-positive nuclei (right two panels) occur after the 11th hr.We also confirmed the presence of caspase-positive granules at 12 hrs but, failing an interpretation of the significance of the granules, we withhold an interpretation. From doctoral research of Farhan S. Khan.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401285&req=5

fig01: The very late appearance of characteristics of apoptosis in metamorphosing insect cells. Upper row: appearance of lysosomes during the involution of the salivary gland of Drosophila, which in our hands has completely collapsed by 13 hrs after the beginning of puparium formation. Monodansylcadaverine detects no resolvable organelles prior to onset of metamorphosis, but by 6 hrs there are numerous perinuclear autophagic vacuoles (arrows) and by 9 hrs the vacuoles fill the cytoplasm (three figures on left). Lysotracker red ® detects modest activity by 9 hrs and large autophagic vacuoles by 12 hrs. Middle row: By 3 hrs into metamorphosis, the fine filamentous actin network, detected by rhodamine phalloidin, has given way to fine granular clumps of actin, which become more pronounced by 9 hrs. By 10 hrs the actin is in vacuoles that appear to be lysosomes, or clustered near the cell membranes. Lower row: Evidence for apoptosis occurs only very late. Both exteriorization of phosphatidylserine as detected by annexin V (left two panels) and appearance of TUNEL-positive nuclei (right two panels) occur after the 11th hr.We also confirmed the presence of caspase-positive granules at 12 hrs but, failing an interpretation of the significance of the granules, we withhold an interpretation. From doctoral research of Farhan S. Khan.
Mentions: There are many alternative paths. Typically, a large, cytoplasm-rich, post-mitotic or poorly mitotic cell such as a mammary epithelial cell has a big problem eliminating its cytoplasm, whereas a small, short-lived, highly mitotic cell subject to many mutagenic situations is more threatening because of its potentially damaged or mutated DNA. Thus apoptosis, with its rapid and complete destruction of DNA, is easily and promptly activated in cells of haematopoietic lineage, while mammary epithelial cells and others undertake massive autophagy. In insects, during metamorphosis the bulk of the larval tissue is destroyed, and cell death is easily timed and is tolerably synchronous. Here, apoptosis is an inconspicuous aspect of the cell death. During metamorphosis, the first 90% of the period during which the cell is dying is occupied by autophagic processes, with no activation of caspases, margination of chromatin, fragmentation of DNA or exteriorization of phosphatidyl serine. At the very end, when almost all cytoplasm has been consumed, one encounters evidence of apoptosis: condensation and margination of chromatin, fragmentation of DNA into nucleosome ladders, exteriorization of phosphatidyl serine and (though insect caspases differ from mammalian caspases and are harder to document) apparent activation of a caspase (Fig. 1). This is what we and others have called autophagic cell death, but it appears today in a different light. Although in the metamorphosing insect nutritional supplies are good (the adult or imaginal tissues are growing rapidly) the larval tissues do not thrive and undergo a type of autophagy that is normally associated with starving cells, cells deprived of trophic hormones or cells that have suffered substantial damage to organelles. It appears that, as in the case in many laboratory experiments, the cell dies only when autophagy fails to sustain it beyond a point of no return. In PC-12 cells deprived of nerve growth factor, the point of no return is the autophagic destruction of all their mitochondria. We do not know the limitation of the larval insect cells. Their tracheae (insect direct-to-cell breathing tubes) collapse and mitochondria are subjected to autophagy, suggesting an energy limitation, but they retain sufficient ATP ultimately to undergo apoptosis. We have no knowledge of the status of hormone receptors or translocators. The suggestion is that the autophagy is a survival mechanism carried beyond its limits.

Bottom Line: Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely-associated and interacting proteins.Another complicating factor is that many death-associated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them.In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, St. John's University, Queens, NY 11439, USA. lockshin@stjohns.edu

ABSTRACT
Cell death is clearly an important factor in development, homeostasis, pathology, and in aging, but medical efforts based on controlling cell death have not become major aspects of medicine. There are several reasons why hopes have been slow to be fulfilled, and they present indications for new directions in research. Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely-associated and interacting proteins. But cells have many options other than apoptosis. These include autophagy, necrosis, atrophy, and stepwise or other alternate means of self-disassembly. The response of a cell to a noxious or otherwise intimidating signal will depend heavily on the history, lineage, and current status of the cell. Many metabolic and other processes adjust the sensitivity of cells to signals, and viruses aggressively attempt to regulate the death of their host cells. Another complicating factor is that many death-associated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them. In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion.

Show MeSH
Related in: MedlinePlus