When the cell undergoes ATP depletion, apoptosis cannot occur and the cell dies by necroptosis (programmed necrosis). In TNFa -induced necroptosis, activation of Complex IIb ( Ripk1 / Ripk3 ) kills the cell without ATP depletion (I think). If in addition to activation of TNFa pathway another pathway that induces apoptosis is active, how does the cell decide to die?
Hi, Herman
Under the situation as you discribe, some cells of the cell pool may perform necroptosis, while some ones of the pool will perform apoptosis, and still others may remain alive but can't divide any more. As for one cell, when it receives death signals from two different origins by different signal pathways, the result may depend on which signal is stronger, which pathway is shorter. Just for reference. Best!
I agree with Yingyu. Even amongst a homogeneous population of cells, there will be a heterogeneous mix of different cell deaths occurring (apoptosis, necrosis, etc), depending on the cell stress. As far as two different signals are concerned, I think the signal that transmits the strongest, in combination with the type of cell stress, determines the cell fate outcome.
For example, I work in primary human skin cells. If I UV irradiate the cells in a dish, some cells die, while others remain attached to the dish. If I perform Annexin V-PI staining and run flow, some cells are in early or late apoptosis, while others are in necrosis. Most of the alive cells are arrested in their cell cycle checkpoint (G1 or G2). For cells that undergo apoptosis, they tend to have more DNA damage compared to cells that undergo necrosis (which also have DNA damage but extensive protein and lipid damage).
Hi, Anne
Thank you for giving us an example in point and sharing with us your work and experience. I think under the situation as Herman discribed, even though some cells performed apoptosis, the golden standard of cell apoptosis-DNA ladder-can not be detected by Agrose gel electrophoresis, genomic DNA smear -a trait of cell necrosis-may be the final outcome, which may be the reason why necropotosis come into our academic world.
Wouldn't it then be important to determine the various populations of cell death, in order to determine if TNF-alpha causes an apoptotic response versus necrosis? Could one say that this response may be a cell-type specific response?
I know that my response comes very in late but I saw that many RG members were / are still interested by this question.
First, I do not think that a "cell decides to die" ... (a rather "humanistic" point of view ...).
Second, the attached articles could be of help.
Best regards
Robert
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