Abstract
Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.
Highlights
Mitochondria serve as cellular signalling hubs and are intimately linked to innate immune signalling pathways[1,2]
These included interferon-stimulated genes (ISGs) involved in immune signalling, such as signal transducer and activator of transcription 1 (STAT1), cyclic GMP–AMP synthase (cGAS), stimulator of interferon genes (STING) or retinoic acid inducible gene I (RIG-I), which all accumulated in Yme1l−/− mouse embryonic fibroblasts (MEFs) (Fig. 1d)
Our results demonstrate that nucleotide metabolism orchestrates mitochondrial DNA (mtDNA)-dependent innate immunity
Summary
Mitochondria serve as cellular signalling hubs and are intimately linked to innate immune signalling pathways[1,2]. Cytosolic mtDNA is recognized by specific receptor proteins, such as cyclic GMP–AMP synthase (cGAS), whose activation triggers the expression of specific interferon-stimulated genes (ISGs) via the adaptor protein stimulator of interferon genes (STING) and the downstream TANK-binding kinase 1 (TBK1)[8,9,10]. This immune response heightens antiviral immunity and protects against nuclear DNA damage[5]. Removal of dysfunctional mitochondria by mitophagy suppresses STING-dependent inflammation and neurodegeneration in mice, a mechanism that might be of relevance in Parkinson’s disease[11]. One of the earliest phenotypes of nervous-system-specific Yme1l knockout mice (NYKO mice) is an inflammatory response in the retina[19], but why the loss of YME1L and impaired mitochondrial proteostasis induce inflammation remains unclear
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