Ribonucleotide incorporation into mitochondrial DNA drives inflammation

Area of Science:

• Biochemistry
• Cell Biology
• Immunology

Background:

• Metabolic dysregulation is linked to inflammatory responses.
• Imbalanced nucleotide synthesis can lead to mitochondrial DNA (mtDNA) release and innate immune activation via cGAS-STING signaling.
• The precise mechanisms by which nucleotide deficiency drives mtDNA-dependent inflammation remain unclear.

Purpose of the Study:

• To elucidate how nucleotide deficiency contributes to mtDNA-dependent inflammation.
• To investigate the role of ribonucleotide misincorporation into mtDNA.
• To explore the link between nucleotide imbalance, senescence, and the senescence-associated secretory phenotype (SASP).

Main Methods:

• Analysis of mtDNA in aged mice lacking MGME1 and in aged wild-type mice.
• Investigation of cells lacking YME1L.
• Study of cell-cycle-arrested senescent cells.
• Assessment of mtDNA release, cGAS-STING activation, and SASP.
• Evaluation of the effects of exogenous deoxyribonucleosides.

Main Results:

• Nucleotide imbalance increases ribonucleotide incorporation into mtDNA, particularly in age-dependent renal inflammation and in aged tissues.
• Reduced deoxyribonucleotide synthesis elevates mtDNA ribonucleotide content in senescent cells.
• This aberrant mtDNA leads to cytosolic release, cGAS-STING activation, and SASP.
• Exogenous deoxyribonucleosides can suppress the observed SASP.

Conclusions:

• Mitochondrial DNA is highly sensitive to aberrant ribonucleotide incorporation.
• Imbalanced nucleotide metabolism drives age- and mtDNA-dependent inflammatory responses.
• Nucleotide imbalance contributes to the senescence-associated secretory phenotype (SASP).