Biochemical controls: cell life or death controls (Introduction)

by David Turell , Friday, June 30, 2023, 15:13 (510 days ago) @ David Turell

AMP plays a major role:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/30_june_2023/411229...

"Maintenance of size and shape of organs in multicellular organisms is determined by the balance between cell proliferation and cell death. It was thought that apoptosis, a mechanism driven by cleavage of intracellular proteins by caspases, was the only genetically programmed cell death pathway. However, it became apparent that necrosis, once regarded merely as an accidental form of cell death, can be a regulated process, with necroptosis being the major subtype. A key player in both apoptosis and necroptosis is receptor-interacting protein kinase 1 (RIPK1). Zhang et al. report that the cellular energy sensor adenosine monophosphate (AMP)–activated protein kinase (AMPK) phosphorylates and inactivates RIPK1, opposing necroptosis and thus promoting cell survival.

"During apoptosis, cell fragments are removed by phagocytic cells in an immunologically silent manner, whereas during necroptosis, cells burst, triggering inflammation. The latter might seem deleterious—indeed, necroptosis is implicated in several inflammatory disorders in humans. However, it has been suggested that necroptosis may have arisen as a backup pathway to kill virus-infected cells, in which viral proteins sometimes inhibit apoptosis.

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"AMPK is expressed in nearly all eukaryotic cells and is switched on by cellular energy stress that it normally senses by detecting increases in AMP relative to ATP (see the figure), although glucose starvation can also be sensed by an AMP-independent mechanism (6). AMPK then phosphorylates numerous downstream target proteins (7), switching on catabolic pathways that generate ATP from adenosine diphosphate (ADP) while switching off ATP-consuming processes, thus preserving cellular energy status and promoting survival.

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"It is becoming apparent that a major function of AMPK is to maintain cellular mitochondrial networks, which are the main source of ATP. When a mitochondrial network becomes damaged, it must first be cleaved into segments small enough to be removed by mitophagy, which AMPK achieves by promoting fission and inhibiting fusion of mitochondria through the phosphorylation of mitochondrial fission factor (MFF) and mitochondrial fission regulator 1 like (MTFR1L), respectively. Next, AMPK activates mitophagy by phosphorylating unc-51–like autophagy-activating kinase (ULK1). Finally, by phosphorylating folliculin-interacting protein 1 (FNIP1), AMPK stimulates both lysosomal and mitochondrial biogenesis—the former to ensure an adequate supply of lysosomes to support mitophagy, and the latter to replace damaged mitochondrial components that had been recycled by mitophagy. How does this fit in with the findings of Zhang et al.? In the longer term, maintenance of the mitochondrial network by AMPK would help to ensure cellular energy homeostasis, thus making it less likely that necroptosis would be promoted by ATP depletion. However, if necroptosis was triggered, the phosphorylation of RIPK1 by AMPK might delay the process to allow time for repair of the mitochondrial network and stave off cell death."

Comment: I've left out the major biochemical discussions of molecular reaction pathways. This yes or no monitoring of cell survival or death is very precise and very complex. It cannot be developed stepwise, so it must be designed all at once, as it is irreducibly complex.