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Mitochondrial DNA damage and Nucleotides availability

mitochondria mtdna nulceotides senescent dna

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#1 dimez1

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Posted 14 October 2019 - 01:16 AM


I stumbled upon two articles that raised my attention on a potential new vector of aging:

 

First one demonstrates that inhibition of nucleotides synthesis pathways forces HMEC (Human Mammary Epithelial Cells) into senescence (assumedly in a G2-exit)
 

Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells
http://www.jbc.org/c...nt/294/27/10564

 

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Second one, recent, explains that mtDNA (Mitochondrial DNA) damage is suspected to negatively affect the repair of the nucleus DNA damages by sequestrating the dNTP (Deoxynucleoside Triphosphate) into the mitochondria while it gets depleted in the cell nucleus.
 

Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias
https://www.nature.c...2255-019-0120-1

 

or the research highlight summary:

mtDNA robs nuclear dNTP
https://www.nature.c...1580-019-0182-7


 

So how might mtDNA damage affect nuclear DNA replication? 
Normally, cellular levels of dNTP increase in preparation for S phase and remain high until DNA replication is completed. But in mutator iPSCs, whole- cell dNTP pools were depleted whereas mitochondrial dNTP pools were enriched, suggesting that following mtDNA damage, cellular dNTPs are sequestered into mitochondria to enhance mtDNA replication. The resulting dNTP depletion in the nucleus would lead to nuclear DNA damage. Indeed, slowing down mtDNA replication reduced the accumulation of dsDNA breaks and improved genome stability. This study presents a new view of how mitochondrial dysfunction might contribute to ageing, by linking increased mtDNA replication to nuclear DNA replication stress and genome instability — another hallmark of ageing.


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What are your thoughts regarding slowing down mtDNA replication?

What are your thoughts regarding enhancing nucleotides synthesis in the aging body?
Folic acid intake is key to nucleotides synthesis but too much of it can increase risk in certain type of cancers (Folate and its impact of Cancer Riskhttps://www.ncbi.nlm...les/PMC6132377/)


#2 William Sterog

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Posted 18 October 2019 - 12:12 PM

Dietary nucleotides extend the life span in Sprague-Dawley rats.

https://www.ncbi.nlm...ubmed/23459974/

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Also tagged with one or more of these keywords: mitochondria, mtdna, nulceotides, senescent, dna

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