Link Between Mitochondrial Nucleotide Balance and Age-Related Inflammation

Recent research conducted by the Max Planck Institute for Biology of Aging in Cologne has uncovered a critical link between mitochondrial nucleotide incorporation and inflammation associated with aging. The study reveals that the improper integration of ribonucleotides into mitochondrial DNA (mtDNA) initiates an inflammatory response that may contribute to age-related diseases.

Mitochondria, often called the powerhouses of the cell, are essential for energy production and cellular signaling. Their dysfunction has been associated with aging, inflammation, and various diseases. Specifically, the activation of the innate immune pathway cGAS-STING, which detects DNA in abnormal locations, can shift from a protective response to a chronic inflammatory state. This sustained inflammation is implicated in autoimmune conditions, tissue degeneration, neurodegeneration, and cancer.

The integrity of mtDNA relies heavily on balanced nucleotide pools, namely ribonucleotide triphosphates (rNTPs) and deoxyribonucleoside triphosphates (dNTPs). rNTPs are vital for RNA synthesis and energy transfer, while dNTPs serve as building blocks for DNA replication and repair. Imbalances in these pools, particularly an increase in rNTPs relative to dNTPs, have been associated with aging tissues and cellular senescence.

The new study, published in Nature, investigates how alterations in nucleotide ratios impact mitochondrial DNA stability and immune activation. Experiments with mice, including those with deficiencies in the enzyme MGME1 responsible for mtDNA maintenance, showed that elevated rNTP to dNTP ratios correlated with increased mitochondrial inflammation. Similar effects were observed in senescent human fibroblasts and aged animal tissues.

Researchers manipulated nucleotide pools in cells and found that reducing dNTP levels or increasing rNTPs promotes mitochondrial DNA damage, triggering the cGAS-STING pathway and inflammation. Conversely, increasing dNTPs through supplementation or gene modulation decreased immune activation. These findings suggest that the imbalance of mitochondrial nucleotide pools during aging fosters a cycle of DNA damage and immune response.

Interestingly, mitochondria lack known mechanisms to properly balance nucleotide incorporation into mtDNA. This deficiency makes mtDNA particularly susceptible to ribonucleotide accumulation, fueling chronic inflammation and tissue deterioration. Future strategies aimed at restoring nucleotide balance or removing damaged mitochondrial DNA may offer new avenues to delay aging effects and treat age-related diseases such as neurodegeneration, kidney disorders, and cancers.