I recently read a paper Ribonucleotide incorporation into mitochondrial DNA drives inflammation which I found very interesting. The reason I found it interesting is perhaps summarised in the first paragraph of the discussion section which I will quote:
I was aware that there was quite a bit of old research that indicated that supplementing the diet with yeast extract and/or DNA extended life, but it was not clear how this worked. It now seems clear that the reason it worked was that it protects mtDNA from replicating wrongly. The challenge, however, is to ensure that the correct nutrients are supplied to ensure that dNTP is available when replicating mtDNA. This is not as easy as it sounds.
We demonstrate that increased incorporation of rNTPs into mtDNA during replication leads to the release of mtDNA fragments from mitochondria and proinflammatory signalling. Our results therefore highlight the challenge that the high molar excess of rNTPs relative to dNTPs poses to cells. Although RNase H2 removes incorporated rNMPs from nuclear DNA as part of the ribonucleotide excision repair pathway, this repair mechanism is not present in mitochondria, which are therefore prone to accumulating rNMPs in their genome. Similar to the effect of rNMPs on nuclear DNA replication27,40, due to the inherent reactivity of the 2′-OH group of the ribose ring or collisions with the replication fork, misincorporated rNMPs may cause DNA strand breaks during replication, priming the release of mtDNA fragments from mitochondria.rNTP is an ribonucleotide triphosphate. These are the building blocks of RNA whilst dNTP is deoxynucleoside triphosphate which are the building blocks of DNA. So simplifying what is going on when mtDNA is being replicated if there is not enough of the DNA bricks an RNA brick is used. At a later point because mtDNA cannot be fixed to remove the RNA the replication process goes wrong and the mtDNA is ejected from the mitochondria. However, in the mean time we have completely wrong mtDNA.
I was aware that there was quite a bit of old research that indicated that supplementing the diet with yeast extract and/or DNA extended life, but it was not clear how this worked. It now seems clear that the reason it worked was that it protects mtDNA from replicating wrongly. The challenge, however, is to ensure that the correct nutrients are supplied to ensure that dNTP is available when replicating mtDNA. This is not as easy as it sounds.
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