Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases

Abstract

Mitochondria play a central role in multiple cellular functions, including energy production, calcium homeostasis, and cell death. Currently, growing evidence indicates the vital roles of mitochondria in triggering and maintaining inflammation. Chronic inflammation without microbial infection - termed sterile inflammation - is strongly involved in the development of heart failure. Sterile inflammation is triggered by the activation of pattern recognition receptors (PRRs) that sense endogenous ligands called damage-associated molecular patterns (DAMPs). Mitochondria release multiple DAMPs including mitochondrial DNA, peptides, and lipids, which induce inflammation via the stimulation of multiple PRRs. Among the mitochondrial DAMPs, mitochondrial DNA (mtDNA) is currently highlighted as the DAMP that mediates the activation of multiple PRRs, including Toll-like receptor 9, Nod-like receptors, and cyclic GMP-AMP synthetase/stimulator of interferon gene pathways. These PRR signalling pathways, in turn, lead to the activation of nuclear factor-κB and interferon regulatory factor, which enhances the transcriptional activity of inflammatory cytokines and interferons, and induces the recruitment of inflammatory cells. As the heart is an organ comprising abundant mitochondria for its ATP consumption (needed to maintain constant cyclic contraction and relaxation), the generation of massive amounts of mitochondrial radical oxygen species and mitochondrial DAMPs are predicted to occur and promote cardiac inflammation. Here, we will focus on the role of mtDNA in cardiac inflammation and review the mechanism and pathological significance of mtDNA-induced inflammatory responses in cardiac diseases.

Keywords: cardiovascular disease; inflammation; mtDNA.

Figure 1.. Mitochondrial DNA and cardiac inflammation.

mtDNA binds to TFAM and is stabilized in cardiac cells, including cardiomyocytes, cardiac fibroblasts, and endothelial cells. Increase of mtROS during stress stimulation leads to oxidation of mtDNA and dissociation of TFAM. Oxidized mtDNA is released via the mitochondrial permeability transition pore (MPTP), whose opening is regulated by cyclophilin D. Damaged mitochondria are degraded by the autophagic process, mitophagy, and detoxified. When this process is impaired, mtDNA inside the autolysosome escape degradation and stimulate TLR9 to induce NF-κB activation, which causes transcriptional activation of multiple inflammatory cytokines (IL-6, TNF-α, pro-IL-1β, and pro-IL-18). NF-κB activation also enhances transcription of NLRP3 to prime inflammasome activation. Increased NLRP3 senses mtDNA and forms a protein complex called inflammasome with ASC and pro-caspase 1, which finally activates caspase 1 to cleave to pro-IL-1β and pro-IL-18 to transform these molecules into bioactive cytokines. Secreted inflammatory cytokines from cardiac cells mediate recruitment of inflammatory cells and cardiac sterile inflammation. cGAS senses mtDNA and activates interferon-related factors to increase transcriptional activities of type I interferons, which cause cardiac inflammation. On the other hand, extracellular mtDNA is released and circulates inside vessels as cell-free mtDNA when the plasma membrane is disrupted by tissue damage, and necrotic cell death is induced. In the serum, mtDNA is observed within exosomes, TFAM-bound forms (nucleoids), or inside neutrophil extracellular traps (NETs). mtDNA enters the endocytic pathway by endocytosis and stimulates endosomal TLR9, which leads to NF-κB activations and inflammasome formation. These processes can be involved in the development of cardiac sterile inflammation.