As I see it part of the issue is to support the dNTP salvage pathway in the mitochondria to the extent that it is not necessarily a large amount of additional dNTP (particularly other than adenosine) as when you get that into the mitochondrion it will be recycled.
We both agree that RNR is less expressed in non-dividing cells which don’t have stress and I learnt today on reading up on this that if acetylation levels are high (meaning high efficiency) then RNR will be inhibiIted in its function even if still expressed.
The question is what happens with consuming ribo-nucleotides. MT1621 in a sense gives some answers as it demonstrates that even people without a functioning pyrimidine salvage pathway can actually maintain mtDNA after birth up to a point (even though the disease is often fatal) and merely from the operation of RNR.
Currently, there are approximately 200 individuals with TK2d that have been identified worldwide. In about 80% of these patients, the age of onset is less than 12 years of age. For early-onset patients, symptoms tend to be more aggressive and the disease is often fatal. There is currently no targeted therapy for TK2d.
I am currently working on the assumption that consuming DNA is better than RNA (even if you have some RNA with the DNA).
Obviously rATP levels are driven primarily by energy levels in the cells and as the ratio of rNTPs is kept reasonably consistent the other bases will also be driven by energy levels.
Hence I would be interested to see examples of where reasonable levels of RNA supplementation (of some status of phosphorylation) has actually caused a deterioration in the rNTP/dNTP ratio.
I accept, however, at high dosage that would be quite likely and for people without the mitochondrial pyrimidine salvage pathway it could possible do more harm than good.
ChatGPT’s summary of research of harm from ribo supplementation basically points a finger at urate
Practical takeaways
- If you have gout, hyperuricemia, kidney stones, CKD, or are on diuretics, avoid high-purine RNA/nucleotide products (e.g., brewer’s yeast or “RNA/DNA” tablets) or use only with monitoring. The risk pathway is via uric-acid elevation, which is well documented in humans. ScienceDirect+1
- For healthy adults, brief nucleotide supplementation mainly shows uric-acid increases; longer-term harm data are sparse. If using, keep doses modest and check serum urate if you notice joint pain or have risk factors.
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I thought I would experiment with Claude and the pubmed connector so I have signed up for a month of access. I asked a question about RNR and got this shareable response
https://claude.ai/public/artifacts/d20c9fb6-6637-4d95-92ce-5a42a7a4115b
The key poinit in this, however, is that RNR continues to operate in post mitotic cells providing dNTPs for mtDNA. (in addition to the salvage pathway)
