FIGURE 3.

Metabolic consequences of mtDNA release and innate immune signaling. Viral infection, either by DNA or RNA viruses, leads to the activation of TBK1 and subsequent phosphorylation of IRF3/7 to induce their nuclear translocation to activate type I interferons. The interferon stimulated genes (ISGs) prevent viral growth, either by direct inhibition of viral replication, termed here “effector ISGs,” or indirectly by rewiring mitochondrial and cellular metabolism (“helper ISGs”). The latter could be achieved by inducing metabolic conditions supporting/favouring the release of mtDNA (left panel). Nucleotide deficiency induced by loss of YME1L or treatment with thymidylate synthase (TS) inhibitor 5-FU leads to the release of mtDNA. TREX1 competes with cGAS for the binding and degradation of mitochondrial dsDNA to single nucleotides, replenishing cellular nucleotide pools in the process. cGAS binding of mtDNA generates cGAMP to activate STING-induced autophagy, independent of TBK1 activation, and innate immunity, by LC3 lipidation and autophagosome formation. The autophagy/lysosome system further contribute to the replenishment of cytosolic nucleotide pools (right panel). Created with BioRender.com.