Metabolism and Innate Immunity Meet at the Mitochondria

Abstract

Mitochondria are master regulators of metabolism and have emerged as key signalling organelles of the innate immune system. Each mitochondrion harbours potent agonists of inflammation, including mitochondrial DNA (mtDNA), which are normally shielded from the rest of the cell and extracellular environment and therefore do not elicit detrimental inflammatory cascades. Mitochondrial damage and dysfunction can lead to the cytosolic and extracellular exposure of mtDNA, which triggers inflammation in a number of diseases including autoimmune neurodegenerative disorders. However, recent research has revealed that the extra-mitochondrial exposure of mtDNA is not solely a negative consequence of mitochondrial damage and pointed to an active role of mitochondria in innate immunity. Metabolic cues including nucleotide imbalance can stimulate the release of mtDNA from mitochondria in order to drive a type I interferon response. Moreover, important effectors of the innate immune response to pathogen infection, such as the mitochondrial antiviral signalling protein (MAVS), are located at the mitochondrial surface and modulated by the cellular metabolic status and mitochondrial dynamics. In this review, we explore how and why metabolism and innate immunity converge at the mitochondria and describe how mitochondria orchestrate innate immune signalling pathways in different metabolic scenarios. Understanding how cellular metabolism and metabolic programming of mitochondria are translated into innate immune responses bears relevance to a broad range of human diseases including cancer.

Keywords: CGAS; MAVS; STING; innate immunity; metabolism; mitochondria; mitochondrial DNA.

FIGURE 1

Mitochondrial antiviral signalling protein regulation induced by glucose metabolism and mitochondrial dynamics. During viral infection MAVS aggregation is essential for mounting an IFN response to suppress viral replication. Glucose and lactate levels (together with NLRX1) are negative regulators of MAVS aggregation (left panel). The right panel illustrates the pivotal role of mitochondrial dynamics in mounting an IFN response during viral infection. Inducing mitochondrial tubulation by expressing MFN2 or preventing DRP1 mitochondrial localisation mediated by DDHA2, as well as treating cells with the DHODH inhibitor leflunomide (LEF), supports MAVS aggregation and subsequent IFN response. Δψ, mitochondrial membrane potential. Created with BioRender.com.

FIGURE 2

Release of mtDNA/RNA and the induction of innate immunity. Stressors, genetic, and metabolic perturbations triggering mtDNA/RNA-dependent innate immune responses. Fragments of mtDNA and mitochondrial nucleoids can be released along different pathways. VDAC oligomerisation at the OM allows the release of mtDNA fragments, which also requires concurrent opening of the mPTP in the mitochondria of ENDOG^–/– cells and neurons expressing mutant mitochondrial localised TDP-43. Oxidised mtDNA fragments are also released in macrophages undergoing excessive mtDNA replication and trigger the NLRP3 inflammasome. TFAM-bound mtDNA nucleoids are released from mitochondria in response to cell death signalling upon herniation of the IM through BAX/BAK pores in the OM. If the cell does not undergo apoptosis, the cytosolic mtDNA triggers innate immune signalling upon recognition by DNA-binding receptors including cGAS and TLR-9. BAX/BAK pores also facilitate the release of mtRNA from mitochondria that have been exposed to stressors which cause double-stranded breaks in mtDNA. Cytosolic mtRNA is recognised by RIG-I and triggers a RIG-I-MAVS-dependent innate immune response. Created with BioRender.com.

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.