Mitochondrial DNA in the regulation of innate immune responses - PubMed (original) (raw)

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Mitochondrial DNA in the regulation of innate immune responses

Chunju Fang et al. Protein Cell. 2016 Jan.

Abstract

Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and considered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor’s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA (mtDNA) activates several innate immune pathways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibacterial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production,mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.

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Figure 1

Figure 1

Mechanisms by which mitochondrial DNA activates innate immunity. Mitochondrial DNA (mtDNA) released from mitochondria following cell damage and stress (e.g. cationic carriers) can activate TLR9 in endosomes, leading to the transcription of pro-inflammatory cytokine genes and increased release of pro-inflammatory cytokines, including MMP-8, TNF-α, IL-6 and IL-1β. In addition, mtDNA escaped into the cytosol after herpes virus infection, can be detected by the cGAS-cGAMP-STING pathway, which results in TBK1-IRF3-dependent expression of type I interferon (IFN I) and dampening viral replication. However, the activation of caspases involved in the intrinsic pathway of apoptosis (caspase-3, caspase-7 and caspase-9) can prevent the activation of IFN response. Moreover, stimulation such as ATP induces mitochondrial dysfunction resulting in mtDNA release into the cytoplasm, where it binds to and activates the NLRP3 inflammasome. Interaction with the adaptor protein Asc and procaspase-1, the NLRP3 inflammasome enables the recruitment and activation of caspase-1, which cleaves pro-IL-1β and pro-IL-18 into their bioactive mature forms. On the other hand, microtubule-associated protein 1 light chain 3B (LC3B)/Beclin 1-mediated autophagy are involved in the clearance of mtDNA, and thus negatively regulating the NLRP3 inflammasome activation

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