Cell Death is Organized Crime: Can We Stop the Killer?

<span class ="caption"> Hepatocytes labeled with fluorescent probes </span>” src=”–/YXBwaWQ9aGlnaGxhbmRlcjt3PTk2MDtoPTUxOC42NjY2NjY2NjY2NjY2/–~B/aD03Nzg7dz0xNDQwO2FwcGlkPXl0YWNoeW9u/″ data-src=”–/YXBwaWQ9aGlnaGxhbmRlcjt3PTk2MDtoPTUxOC42NjY2NjY2NjY2NjY2/–~B/aD03Nzg7dz0xNDQwO2FwcGlkPXl0YWNoeW9u/″/></p>
<p>Hepatocytes labeled with fluorescent probes</p>
<p>Life and death are two inseparable companions, facing each other, both knowing that one would not be possible without the other existing.  Every living being, sooner or later, will face its inexorable end.  Cells are the fundamental units of life and the simplest organization identified as living.  Therefore, they could not be the exception to such a fateful destiny.</p>
<h2>Cell death, a programmed process at the molecular level</h2>
<p>Science has been able to conclude that cell death occurs in an orderly, organized and perfectly executed way thanks to the activity of multiple proteins.</p>
<p>These proteins behave like professional killers and cooperate with each other to commit a merciless crime.  However, the modus operandi and the executioners who execute such an abject plan may be different depending on the physiological or pathophysiological context in which the death of the cells takes place.</p>
<p>This is the reason why we scientists classify cell death in different modalities, according to its particular execution mechanism.  A catalog of forms of death whose molecular details we are only beginning to understand.</p>
<h2>An unstoppable wave</h2>
<p>The biology of cell death has always fascinated scientists.  In 2018, a study published in the journal Science showed how death traveled through the cells of the Xenopus laevis frog at a speed of approximately 30 micrometers per second.</p>
<p>They achieved this milestone by fluorescently labeling the proteins involved in the death of these cells.  In this way, they observed how death advanced through the cell like an unstoppable wave of molecular events.  A wave that was propelled at every step activating killer proteins.  A wave that reached the last corner of the cell and led it to its complete destruction.  “Like fire spreading through the countryside”, in the words of the authors themselves.</p>
<h2>Apoptosis, a form of cell suicide</h2>
<p>Read more</p>
<p>However, what the authors observed in this study was not exactly a crime, but rather a suicide.  They fluorescently labeled proteins involved in apoptosis, a type of cell death activated by cells themselves to avoid a greater evil.  Die so that others can continue living.</p>
<p>Cells respond in this way, for example when they have mutated and there is a risk that they will transform into tumor cells.  Also to prevent an infection from spreading or simply to make tissue regeneration a reality.  Cells also die by apoptosis during embryonic development, to sculpt the anatomy of the future individual in the amorphous mass.</p>
<p>The altruism of this form of cell death requires that it not have negative consequences for the rest of the body.  It must be a clean kill.  To do this, macrophages, unless they are saturated, will clean up the remains of the death with enough speed so that no undesirable immune response is activated.</p>
<h2>Necrosis is also organized at the molecular level</h2>
<p>Unfortunately, not all types of death are so quiet.  The real crimes happen in cells in the form of death by necrosis.  Necrosis is a type of death that was traditionally considered to occur by chance.  For example, as a result of trauma or a burn.</p>
<p>In this type of death, when the cell membrane ruptures abruptly, the intracellular components are massively released into the extracellular space and this causes a systemic inflammatory response.  Therefore, unlike apoptosis, necrosis is an uncontrolled death that causes great damage to the body.</p>
<p>In 2005, researcher Junying Yuan concluded that death from necrosis was not always an accident, it could also be organized crime.  He observed that by inhibiting the RIPK1 protein, necrosis stopped.</p>
<p>He had discovered a new type of programmed cell death, necroptosis, and had identified the main perpetrator.</p>
<p>It has been during the last decade that the true executor of necroptosis, the MLKL protein, has been identified.  When RIPK1 is activated, the MLKL protein polymerizes to form a pore-shaped structure that pierces the plasma membrane and destroys cell integrity.  The crime has been consummated and the consequences for the individual will not be long in coming.</p>
<h2>Can we intervene in cell death?</h2>
<p>Along with the concept of necroptosis, others such as piroptosis, ferroptosis or netosis have evolved.  At present, the classification of cell types of death is routinely reviewed and this is of special relevance since it shows that cell death is not a singular event.  On the contrary, it happens in multiple ways.</p>
<p>Therefore, we must investigate what specific form of death occurs in the majority in each type of disease if we want to move towards more effective therapies.</p>
<p>Taking into account that cell death processes are programmed phenomena at the biochemical level, it is possible that we can intervene pharmacologically on them.  For this, it is essential to know in detail the mechanisms that operate in each subtype of death.</p>
<p>Discovering the murderer, being able to head off the criminal organization, will help us stop crime and prolong, at least for some time, cell survival.</p>
<p>This article was originally published on The Conversation.  Read the original.</p>
<p>The signatories are not salaried, or consultants, nor do they own shares, nor do they receive financing from any company or organization that can obtain benefit from this article, and they have declared that they lack relevant links beyond the academic position mentioned above.</p>
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