Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity

Area of Science:

• Immunology
• Cell Biology
• Metabolic Regulation

Background:

• Cytosolic mitochondrial DNA (mtDNA) activates type I interferon responses, but triggers for mtDNA release are unknown.
• The cyclic GMP-AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS-STING-TBK1) pathway mediates mtDNA-dependent immune signaling.

Purpose of the Study:

• To investigate the metabolic control of mtDNA release and subsequent innate immune signaling.
• To identify the molecular mechanisms linking cellular metabolism to immune activation via cytosolic mtDNA.

Main Methods:

• Investigated the role of the mitochondrial protease YME1L in pyrimidine metabolism and mtDNA release.
• Utilized cell culture and mouse models to study inflammation in response to YME1L deficiency.
• Examined the involvement of the cGAS-STING-TBK1 pathway and SLC25A33 in mtDNA-induced immune responses.
• Assessed the impact of pyrimidine pool replenishment on immune signaling.

Main Results:

• YME1L deficiency leads to pyrimidine depletion, causing mtDNA release and cGAS-STING-TBK1-dependent inflammation in mouse retinas and cell cultures.
• The immune response requires SLC25A33 and is suppressed by restoring pyrimidine levels.
• Overexpression of SLC25A33 or inhibition of de novo pyrimidine synthesis induces mtDNA-dependent immune signaling.

Conclusions:

• Cellular pyrimidine deficiency is a key trigger for mtDNA release and innate immune activation.
• The YME1L-SLC25A33 axis plays a crucial role in maintaining pyrimidine homeostasis and preventing aberrant immune responses.
• mtDNA release and subsequent immune signaling represent a metabolic response to pyrimidine shortages.