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Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases

Research output: Contribution to journalReview article

Kinya Otsu, Hiroyuki Nakayama

Original languageEnglish
Article number475
Pages (from-to)839-852
JournalBiochemical J
DOIs
Publication statusPublished - 15 Mar 2018

Documents

  • main180201

    main180201.pdf, 472 KB, application/pdf

    16/02/2018

    Accepted author manuscript

    CC BY

King's Authors

Abstract

Mitochondria play a central role in multiple cellular functions, including energy
production, calcium homeostasis, and cell death. Currently, growing evidence indicate 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/STING 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 as well as 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.

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