Nature reports new findings from the Max Planck Institute for Biology of Aging in Cologne, showing that the mistaken insertion of ribonucleotides into mitochondrial DNA (mtDNA) sparks an inflammatory response.
Mitochondria are essential for cell survival, providing metabolic output and signaling capabilities. When they malfunction, inflammation, cell death and disease can follow.
The innate immune pathway cGAS–STING–TBK1 can shift a cell from a short-term defense mode into chronic alarm. This pathway is implicated in autoimmune and inflammatory disorders and also contributes to cellular senescence and aging, linking immune signaling to tissue decline.
Senescent cells acquire a secretory phenotype that sustains inflammation and can disturb local tissue function. cGAS–STING–driven inflammation has also been described in neurodegenerative processes associated with aging, connecting innate immune cues to nervous‑system vulnerability.
Mitochondrial function depends on nucleotide building blocks. Ribonucleotide triphosphates (rNTPs) build RNA, while deoxyribonucleotide triphosphates (dNTPs) are required for DNA construction and repair. DNA polymerases use dNTPs during replication, whereas rNTPs such as ATP and GTP are used in energy transfer and signaling.
How an imbalance between rNTPs and dNTPs might affect mtDNA, and whether this has physiological significance during aging, remains unclear.
In the study titled "Ribonucleotide incorporation into mitochondrial DNA drives inflammation," the research team investigated the impact of nucleotide imbalance on mtDNA integrity and immune activation.
Mouse cohorts comprised wild‑type and MGME1‑deficient animals examined at various ages. MGME1 is an enzyme that maintains the mitochondrial genome during replication and repair.
Increased rNTP to dNTP ratios were linked to MGME1 loss and inflammatory markers throughout the study.
MGME1‑deficient cells displayed a higher rNTP/dNTP ratio in metabolite analyses. A further reduction of the mitochondrial protease YME1L or exposure to 5‑fluorouracil produced comparable ratio shifts.
Human fibroblasts induced into senescence by irradiation or drug treatment also showed elevated rNTP/dNTP ratios. Older mouse tissues—including kidney, liver, heart and spleen—had higher ratios than younger tissues.
Altering this ratio modified inflammatory outcomes. Reducing SAMHD1, which increases dNTP pools, lowered cGAS–STING activation in MGME1‑deficient cells.
Adding deoxyribonucleosides, which raise intracellular dNTP levels, dampened cGAS–STING‑related inflammatory gene expression in senescent cells.
The authors conclude that mtDNA susceptibility to ribonucleotide imbalance represents a mechanism that links disrupted nucleotide metabolism to innate immune activation. Their findings suggest that accumulated ribonucleotides in mtDNA during aging and senescence drive cGAS–STING–mediated inflammation, with potential implications for kidney disease, neurodegeneration and cancer.
MtDNA has no recognized nucleotide‑balancing system, though such pathways may yet be uncovered. If mitochondria cannot self‑regulate, perhaps future research will provide that equilibrium.
Removing “mitochondrial trash” could prolong healthy function of mitochondria, cells, tissues and, by extension, extend human lifespan.