From a mechanistic perspective, however, the real time changes are very interesting.
Looking, for example, at the differentiation of stem cells. We start with a cell which has complex 1 inhibited and depends upon pyruvate to maintain redox status. Then (and there is some link here to coming out of a hypoxic environment) it moves towards differentiation, NF kappa B is turned right up creating a substantial citrate flux from the mitochondria and large scale acetylation occurs to enable differentiation. It is at this point that differentiation can fail and the cell enter senescence. It would be nice to understand this at a lower level, but I don’t think it can be measured properly.
Acetyl-CoA is also part of the cell division process and I would like to fully understand the process whereby cells move from a single stem cell to a daughter cell and continuing stem cell.
chatGPT has given me a bit of an answer on this.
Acetyl-CoA is more than a metabolic intermediate; during proliferation it acts as a three-way hub that couples carbon availability to the nuclear, cytosolic and membrane-building events that let a cell duplicate itself.
| Pillar |
What happens |
Why acetyl-CoA is indispensable |
| 1. Epigenetic ignition of the cell-cycle engine |
The first wave of genes needed for G1/S entry—including the yeast G1 cyclin CLN3 and hundreds of “growth” genes—are switched on only when their promoters become hyper-acetylated. That burst of acetyl marks is limited by how much acetyl-CoA is present in the nucleus; boosting acetyl-CoA drives histone acetylation and cell-cycle entry, while starving it keeps chromatin closed and the cycle off. |
• Acetyl-CoA directly fuels GCN5/CBP/p300 histone acetyl-transferases.
• Local nuclear production by ATP-citrate lyase (ACLY) or acetyl-CoA synthetase (ACSS2) ensures that histone acetylation can spike even when cytosolic levels are low. (考研, Nature) |
| 2. Building blocks for two daughters |
Every round of division roughly doubles plasma-membrane area, ER and Golgi surface, and the lipid sleeve that envelopes segregating chromosomes. All of that membrane is built from fatty acids and sterols that start as cytosolic acetyl-CoA. |
• Cytosolic acetyl-CoA (mainly from ACLY) is converted by ACC → FASN → elongases/desaturases into phospholipids and neutral lipids.
• Knocking down ACLY, blocking ACC, or inhibiting FASN stalls cells in G1 or kills them because membrane mass cannot keep pace; a 2024 study even uncovered a “lipid checkpoint” in early G1 that arrests the cycle when fatty-acid synthesis (and thus acetyl-CoA consumption) is inadequate. (考研, Nature) |
| 3. Acetylation as a molecular timer |
Many cell-cycle regulators themselves are acetylated. For example, Cyclin A must be acetylated at specific lysines before the APC/C can ubiquitinate and destroy it, ensuring orderly mitotic exit. Tubulin and several CDKs are similarly controlled. Because acetyl-CoA is the acetyl donor, its concentration influences how quickly these timers tick. |
• When acetyl-CoA is limiting, cyclin acetylation and degradation slow, lengthening mitosis; excess acetyl-CoA has the opposite effect. (考研) |
How the three arms are coordinated
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Nutrient sensing → acetyl-CoA synthesis. Growth-factor signalling (PI3K–mTOR) up-regulates ACLY and ACLY’s citrate supply; AMPK and PGC-1α fine-tune ACSS2 and mitochondrial export, ensuring that carbon flows to acetyl-CoA only when energy is adequate.
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Spatial pools matter. Nuclear ACLY/ACSS2 complexes generate an “on-site” pool for chromatin, while cytosolic ACLY feeds ACC/FASN for lipids. Compartmentalisation lets a cell prioritise gene activation even when membrane synthesis must pause, and vice-versa.
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Feedback to checkpoints.
- Histone acetylation of cyclin-D/E promoters activates CDK4/6 → Rb phosphorylation → S-phase entry.
- The G1 lipid checkpoint senses incomplete fatty-acid synthesis (a proxy for low acetyl-CoA flux) and activates PERK–ATF4 → p21, blocking CDK activity until lipid supply recovers.
Big-picture view
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Signal Acetyl-CoA levels rise in response to carbon and growth signals.
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Set chromatin Local nuclear acetyl-CoA spikes open proliferation genes.
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Supply biomass Cytosolic acetyl-CoA is channelled into fatty-acid/cholesterol synthesis so the cell can physically double.
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Synchronise timing Acetyl-CoA-dependent acetylation of cyclins/CDKs/microtubules ensures each phase ends only when the previous one is metabolically “paid for.”
Because all three roles depend on the same metabolite, perturbing acetyl-CoA synthesis or utilisation (e.g., with ACLY inhibitors) simultaneously starves chromatin remodelling, lipid supply and cell-cycle timing—explaining why such enzymes are promising anti-proliferative drug targets in cancer and why acetate supplementation can sometimes rescue dividing cells under metabolic stress.
In short: acetyl-CoA acts as the metabolic throttle of cell division, translating carbon abundance into the chromatin state, macromolecular building blocks and molecular timers that collectively allow one cell to become two.
We have 4 people willing to put the money into this. Just waiting for a response from Ora on this one to get it started.
I thought I would ask chatGPT for a bit more on the process of differentiation of stem cells. I suppose it is not really relevant to this thread as C Elegans adult cells don’t divide.
Hence I have put that here:
