Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate 
immunity

Sprenger, H.-G.; MacVicar, T.; Bahat, A.; Fiedler, K. U.; Hermans, S.; Ehrentraut, D.; Ried, K.; Milenkovic, D.; Bonekamp, N.; Larsson, N.G.; Nolte, H.; Giavalisco, P.; Langer, T.

doi:10.1038/s42255-021-00385-9

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Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity

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Sprenger, H.-G.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons278027

MacVicar, T.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons278138

Bahat, A.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons281122

Fiedler, K. U.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons281124

Hermans, S.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons281126

Ehrentraut, D.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons281128

Ried, K.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons129408

Milenkovic, D.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons129384

Bonekamp, N.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons129342

Larsson, N.G.
Department Larsson - Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons276056

Nolte, H.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons97166

Giavalisco, P.
Metabolomics, Core Facilities, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons278030

Langer, T.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Citation

Sprenger, H.-G., MacVicar, T., Bahat, A., Fiedler, K. U., Hermans, S., Ehrentraut, D., et al. (2021). Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity. Nature Metabolism, 3(5), 636-650. doi:10.1038/s42255-021-00385-9.

Cite as: https://hdl.handle.net/21.11116/0000-000B-2D5D-C

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.