Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases

Hiroyuki Nakayama and Kinya Otsu

http://www.biochemj.org/content/475/5/839.long


In this review, the authors discuss the role of mitochondria, and especially mitochondrial DNA (mtDNA) in triggering and maintaining cardiac inflammation. In this blost post we only summarise some parts of the review directly related to mtDNA.

We all know that the immune system provides protection against microorganisms such as bacteria, viruses, and fungi. This is achieved by sensing both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).

One major mechanism for activating the innate immune system is the sensing of pathogen-derived nucleic acids, and this is where mitochondria come into play. Due to their bacterial origin, mtDNA shares similarities with bacterial DNA (e.g. it contains cardiolipin and a predominantly unmethylated CpG motif). Mitochondria also release other DAMPs which can bind and activate multiple pattern recognition receptors similar to those activated by PAMPs.

MtDNA can leave the mitochondria and enter the cytoplasm or leave the entire cell. Opening of the mitochondrial transition pore plays an important role of mtDNA release from mitochondria, as inhibition of pore opening reduced levels of mtDNA in the cyotosol. MtDNA release is also controlled by other regulatory proteins such as the voltage dependent anion channel, Bax, and Bak.

MtDNA released after cell death functions as a DAMP. The mechanism of releasing mtDNA from non-nectrotic cells remains unclear, though exosomal release is proposed to be involved in this mechanism.  MtDNA enters the endocytic pathway by endocytosis and stimulates pattern recognition receptors which eventually leads to inflammasome formation.

It is important to degrade extracellular mtDNA to inhibit unnecessary inflammatory responses. It could be that mtDNA, like other non-host DNA in circulation, is digested in part by circulating nucleases. It is, however, unclear whether this occurs in physiological conditions, especially when mtDNA exists in microvesicles such as exosomes. Inside cells, DNasell plays an important role in mtDNA degradation


Levels of circulating mtDNA increase with age and correlate with levels of pro-inflammatory cytokines. Therefore, mtDNA-induced inflammatory responses can be involved in age-related cardiovascular disease, heart failure and atherosclerosis.

During heart failure, multiple endogenous DAMPs (including mtDNA) are released and recognized to induce an inflammatory response. However, no associated was found between the severity of heart failure and mtDNA levels in serum of patients (patients do show much higher serum mtDNA levels compared to controls).

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