Research led by the Max Planck Institute for Biology of Aging in Cologne reports that misincorporation of ribonucleotides into mitochondrial DNA (mtDNA) initiates an inflammatory cascade.
Mitochondria support cell survival through metabolic and signaling roles. Conversely, their disruption has been associated with inflammation, cell death and disease.
Innate immune activation through the cGAS-STING-TBK1 pathway can move a cell from short-term defense to a chronic state of alarm. cGAS-STING activity is linked to autoimmune and inflammatory diseases and contributes to senescence and aging, intertwining immune signaling with tissue decline.
Senescent cells then adopt a secretory phenotype that sustains inflammation and can disrupt local tissue function. cGAS-STING-driven inflammation has also been reported in aging-related neurodegeneration, tying innate immune cues to nervous-system vulnerability.
Mitochondrial function relies on nucleotide building blocks to operate. Ribonucleotide triphosphates (rNTPs) and deoxyribonucleotide triphosphates (dNTPs) are the building blocks for RNA and DNA, respectively. ATP, a primary energy source for many cellular processes, is a form of rNTP, as is GTP, which is heavily involved in cell signaling pathways. DNA polymerase uses dNTPs to build and repair new strands of DNA during replication.
Questions persist about how nucleotide imbalance might alter mtDNA and whether such changes hold mechanistic physiological relevance during aging.
In the study, “Ribonucleotide incorporation into mitochondrial DNA drives inflammation,” published in Nature, investigators designed experiments to determine how nucleotide imbalance influences mtDNA integrity and immune signaling.
Mouse cohorts included wild-type and MGME1-deficient animals examined across ages. MGME1 is an enzyme that helps to maintain the integrity of the mitochondrial genome by conducting specific fixes during mtDNA replication and repair.
Rising rNTP to dNTP ratios trended with MGME1 loss and inflammation throughout the study results.
In MGME1-deficient mouse cells, metabolite measurements show a higher rNTP to dNTP ratio. Additional loss of the mitochondrial enzyme YME1L and exposure to 5-fluorouracil produced similar shifts.
Senescent human fibroblasts created by irradiation or drug treatment also showed higher rNTP to dNTP ratios. Aged mouse tissues, including kidney, liver, heart and spleen, showed higher ratios than young tissues.
Manipulating that ratio changed inflammatory outcomes. Lowering SAMHD1, which raises dNTP pools, reduced cGAS–STING activation in MGME1-deficient cells.
Supplementing senescent cells with deoxyribonucleosides, which increases intracellular dNTP pools, reduced cGAS–STING-linked inflammatory gene expression
Authors conclude that vulnerability of mtDNA to ribonucleotide imbalance represents a mechanism linking disturbed nucleotide metabolism to innate immune activation. Findings suggest that accumulation of ribonucleotides in mtDNA during aging and senescence fuels cGAS–STING–driven inflammatory responses, with implications for kidney disease, neurodegeneration and cancer.
mtDNA lacks any known nucleotide balancing mechanism, not that they do not exist, rather any such pathways are still uncharacterized by science. If nature has not provided such a balance, perhaps science one day will.
A method of taking out the “mitochondrial trash” could potentially prolong the healthy function of mitochondria, cells, tissues and, by direct effect, extend the human lifespan.