Scientists have discovered a possible mechanism behind age-related inflammation. It involves wrong building blocks being incorporated into mitochondrial DNA during replication and can be countered by adding the correct ones [1].
Too similar to bacteria
Mitochondria, the cells’ energy-producing organelles, are considered to have developed from bacteria that once entered an ancient cell and stayed, enabling life as we know it [2]. Mitochondria’s microbial origins can still pose a problem: when mitochondrial DNA (mtDNA) gets into the cytoplasm, its resemblance to bacterial DNA might trigger an immune response [3].
Aging is accompanied by an increase in inflammaging, a form of inflammation that is unrelated to infections (sterile inflammation) and that harms cells and tissues [4]. The origins of inflammaging are not entirely understood, but mtDNA leakage has been proposed as a possible culprit. In this new study published in Nature, scientists from the Max Planck Institute for the Biology of Ageing describe a mechanism that might underlie this link.
Their central hypothesis, based on previous research, suggested that when deoxyribonucleoside triphosphates (dNTPs, the proper building blocks for DNA) are scarce relative to ribonucleoside triphosphates (rNTPs, the RNA building blocks), mitochondria mistakenly install rNTPs into mtDNA. These embedded rNTPs make the genome fragile during replication, creating fragments that spill into the cytosol and activate the well-studied inflammatory cGAS-STING pathway.
The wrong building blocks
The team started by using mice lacking MGME1, an enzyme needed for proper mtDNA replication, that naturally develop mtDNA leakage and inflammation. In the mice’s kidneys, they saw increased mtDNA fragment accumulation and innate immune activation, suggesting that the two are causally linked. These mice have been shown to develop kidney disease and die sooner. Knocking out the STING part of the cGAS-STING inflammatory pathway reduced inflammation and ameliorated kidney pathology.
The next question the researchers asked was whether this effect requires active mtDNA copying. When the researchers slowed or blocked mtDNA replication, the inflammatory response decreased, suggesting that the problem stems from breaks during copying rather than ambient damaged DNA. Deep mtDNA sequencing pointed at frequently aborted replication as the source of excessive mtDNA fragmentation.
The study then moved towards determining if the rNTP:dNTP ratio becomes imbalanced in cells where mtDNA copying isn’t working properly. Theoretically, numerous unsuccessful replication attempts should cause the limited dNTP pool in mitochondria to deplete, and this is what the researchers observed. Turning up the dNTP supply by knocking down SAMHD1, a dNTP-depleting enzyme, restored dNTPs and suppressed activation of the immune response.
In a complementary model lacking the mitochondrial protease YME1L, which also perturbs nucleotide metabolism, the researchers showed that raising the rNTP:dNTP ratio slows de novo mtDNA synthesis. They then measured rNMPs in mtDNA directly by two different methods and found that interfering with nucleotide metabolism caused an increase in rNMPs.
Confirmed in senescence and natural aging
The researchers then moved to senescent human fibroblasts, which are known to have decreased activity of RNR, the enzyme that converts rNTPs to dNTPs, and, consequently, a higher rNTP:dNTP ratio. Lowering it by adding back deoxyribonucleosides (dNs) reduced cytosolic mtDNA and caused the senescent cells to become less toxic without actually reversing senescence: a senomorphic effect. The treated fibroblasts produced less of the senescence-associated secretory phenotype (SASP), a mix of mostly pro-inflammatory molecules emitted by senescent cells.
Finally, the team confirmed that older healthy mouse tissues have a higher rNTP:dNTP ratio than younger ones do. This suggests that the mechanism is indeed characteristic of normal aging and is a promising target for future anti-aging interventions.
“Our findings explain on a molecular level how metabolic disturbances can lead to inflammation in senescent cells and in aged tissue and open up new strategies for possible interventions,” said Prof. Thomas Langer, who led the study.
“There is already a therapy for certain mitochondrial diseases that involves administering DNA building blocks. However, we do not yet know if it can also alleviate the inflammation that occurs more frequently with age. It would be interesting to test this,” noted Dusanka Milenkovic, one of the study’s lead authors.
On X, Harvard geroscientist Dr. David Sinclair called the study “an exciting new paper that could explain why inflammation rises as we age.” He added: “The paper shows that during cell stress & as mice age, their cells incorporate the wrong type of bases (ribonucleotides not deoxyribonucleotides) into replicating mDNA, causing the genome to eventually break and leak into the cytoplasm.”
Literature
[1] Bahat, A., Milenkovic, D., Cors, E., Barnett, M., Niftullayev, S., Katsalifis, A., … & Langer, T. (2025). Ribonucleotide incorporation into mitochondrial DNA drives inflammation. Nature, 1-9.
[2] Andersson, G. E., Karlberg, O., Canbäck, B., & Kurland, C. G. (2003). On the origin of mitochondria: a genomics perspective. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 358(1429), 165-179.
[3] Hu, M. M., & Shu, H. B. (2023). Mitochondrial DNA-triggered innate immune response: mechanisms and diseases. Cellular & molecular immunology, 20(12), 1403-1412.
[4] Franceschi, C., Garagnani, P., Vitale, G., Capri, M., & Salvioli, S. (2017). Inflammaging and ‘Garb-aging’. Trends in Endocrinology & Metabolism, 28(3), 199-212.
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