13 September 2024
In the early 90’s one of the most fascinating mysteries of biology attracted my curiosity: the cell’s ability to commit suicide. In my view, the existence of a specific genetic program devoted to regulate the death of a cell is something, still exciting today. At that time identification of genes and the definition of the signaling pathways, controlling cell death was a sort of gold rush. Through the years cell death has emerged as a key process to regulate tissue homeostasis.
I will not discuss about apoptosis or programmed cell death, I am sure that all the readers are familiar with these concepts. Instead, I would like to take the opportunity of reflecting about apoptosis and evolution. Why and how did such program emerged during the evolution? Did the genes involve in the program acquired the killing option, as an additional task or, did they emerged as new elements, specifically involved in the apoptotic process?
Several studies have established that apoptosis arose with the appearance of the multicellular organisms (1) probably as a sort of “health insurance” for living in a community. Despite this, we cannot ignore that multiple connections between apoptosis and cellular responses to pathogens exist. Certain caspases are activated in response to infections and Apaf-1, the cytosolic partner of cytochrome c shares homology with elements of the signaling pathways activated by NOD-like receptors. Hence in principle apoptosis could be emerged in a single cell organism as part of the reaction to invasion, but only in multicellular organisms it provided a dramatic advantage also for other perspectives (removal of damaged or exhausted cells).
We could figure out that the apoptotic program is a sort of branch of the defense response. Clearly this hypothesis does not hold true for all the genes of the program. Cytochrome c for example, the key trigger of the apoptosome assembly and caspase-9 activation is not linked to pathogen defense. Instead cyt c is fundamental for both life and death. The doctor Jekyll and mister Hide paradox.
A still unresolved point regards when and why this ancient gene was involved in apoptosis. Not in C. elegans, probably not in Drosophila too. Hence, we could hypothesize that cyt c and more in general mitochondrial outer membrane permeabilization (MOMP) became involved in apoptosis only with the Chordata. Nevertheless, the example of cyt c tells us that a gene, normally involved in a specific function (life) has been recruited through the evolution for a different task (cell death). Is this the general scheme that holds true also for other elements of the apoptotic program or is the scenario rather multifaceted?
Studies on the synaptic changes that underline memory suggest that a local activation of caspase-3 at the dendrite could be linked to the long-term depression. A phenomenon during which synapses become less sensitive to a stimulus and the dendritic spine shrinks (2). This observation suggests that caspases and components of the apoptotic machinery during the evolution have been engaged in additional roles. Starting from apoptosis to do something else.
An additional example of this multifaceted world is testified by the connection between apoptosis and necrosis. Deletions in mice of each element of the Death Induced Signaling Complex (DISC), responsible for the activation of caspase-8 (FADD, FLIP and Casp-8 itself) are lethal. Mice die in utero, at mid-gestation as a consequence of vascular, cardiac and blood cells defects. This complex phenotype is caused by an uncontrolled necrosis.
A mystery until when a cross-road between apoptosis and necrosis was found in the kinases RIPK1 and RIPK3. RIPKs among the multiple activities control a peculiar necrotic pathway named necroptosis. Caspase-8 can switch-off the RIPKs activity by proteolytic cleavages. Intriguingly, crossing mice with deficiencies in DISC elements with mice defective for RIPKs rescued from the embryonic lethality.
Hence caspase-8 activity is not merely limited to the control of apoptosis, but it is also fundamental to buffer necrosis and thus favoring survival. Another doctor Jekyll and mister Hide paradox. Which came first the anti-necrotic or the pro-apoptotic function? In conclusion, there are several examples where elements of the apoptotic machinery control additional cellular functions. It is possible that in certain issues the second option evolved after the apoptotic role (the function of casp-3 in LTD), but in others the apoptotic activity was the second opportunity.
- Wiens M, et al. Caspase-mediated apoptosis in sponges: cloning and function of the phylogenetic oldest apoptotic proteases from Metazoa. Biochim Biophys Acta. 2003; 1593:179-189.
- Li, Z. et al. Caspase‑3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 2010. 141:859–871.
- Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 2013, 38:209-23
