Immunometabolism

Assessing the role of metabolic reprogramming in innate immune signaling

Mitochondria are organelles that can engage in immune-cell signalling by multiple means:

‍1. Mitochondrial damage can induce cell death and innate immune signalling by releasing cytochrome C or mitochondrial dsRNA, which leads to the activation of cell death (caspase-9 activation) or aninnate immune signalling pathway, such as the cGAS-STING pathway or MDA5-MAVS pathway.

‍2. The outer mitochondrial membrane can serve asa signalling platform for innate immune pathways, such as the RLR family of receptors that utilise the adapter molecule MAVS.

‍3. The synthesis of the anti-microbial metabolite itaconate in pro-inflammatory macrophages inhibits succinate dehydrogenase (SDH) and causes an increase in intracellular succinate levels. Moreover, itaconate poisons the mitochondrial B12 pool and thus inhibit the catabolism of branched-chain amino acids. Finally, itaconate dampens the pro-inflammatory activation.

‍4. Upon activation or under cellular stress conditions mitochondria can release reactive oxygen species (mROS),which has critical functions in cellular signalling. mROS can result in the activation of transcription factors, such as hypoxia-inducible factor 1α (HIF1α), nuclear factor of activated T cells (NFAT) and nuclear factor-κB(NF-κB). Notably, the rate and amount of mROS production is controlled by a variety of factors, including electron transport chain (ETC) flux and the mitochondrial membrane potential, since mROS is primarily produced by complexesI and III of the ETC. Hence, mitochondrial function indirectly, via mROS production, influences transcriptional changes.

‍5. Another mechanism, by which a change in cellular metabolism can influence the quality of the signalling output, is by epigenomic programming of cells. Indeed, alterations to the function of the TCA cycle can generate different concentrations of TCA metabolites, which are essential co-factors or substrates of epigenetic enzymes. For example, the TCA metabolites α-ketoglutarate (αKG) and succinate are the substrate and the product, respectively, of histone demethylase enzymes. Therefore, alterations to the ratio of TCA metabolites can change their availability and thereby inhibit or promote histone demethylation. Another product of the TCA cycle, citrate, is an important metabolite that can be metabolised into different bioactive substances.