The role of mitochondria in the pathogenesis of Kawasaki disease

Abstract

Kawasaki disease is a systemic vasculitis, especially of the coronary arteries, affecting children. Despite extensive research, much is still unknown about the principal driver behind the amplified inflammatory response. We propose mitochondria may play a critical role. Mitochondria serve as a central hub, influencing energy generation, cell proliferation, and bioenergetics. Regulation of these biological processes, however, comes at a price. Release of mitochondrial DNA into the cytoplasm acts as damage-associated molecular patterns, initiating the development of inflammation. As a source of reactive oxygen species, they facilitate activation of the NLRP3 inflammasome. Kawasaki disease involves many of these inflammatory pathways. Progressive mitochondrial dysfunction alters the activity of immune cells and may play a role in the pathogenesis of Kawasaki disease. Because they contain their own genome, mitochondria are susceptible to mutation which can propagate their dysfunction and immunostimulatory potential. Population-specific variants in mitochondrial DNA have also been linked to racial disparities in disease risk and treatment response. Our objective is to critically examine the current literature of mitochondria's role in coordinating proinflammatory signaling pathways, focusing on potential mitochondrial dysfunction in Kawasaki disease. No association between impaired mitochondrial function and Kawasaki disease exists, but we suggest a relationship between the two. We hypothesize a framework of mitochondrial determinants that may contribute to ethnic/racial disparities in the progression of Kawasaki disease.

Keywords: Kawasaki disease; inflammasome; inflammation; mitochondria; mitochondrial DNA; mitophagy; reactive oxygen species.

Figure 1

Viral and Bacterial Targeting of MitochondriaSchematic representation of role of mitochondria in immune signaling upon viral (blue) or bacterial (red) infection. Exposure to viruses or bacteria both activate immune responses by altering mitochondrial dynamics, namely the NLRP3 inflammasome (orange). Upon viral infection, mitochondrial antiviral-signaling protein (MAVS) is located in the outer mitochondrial membrane and serves as an important signaling. MAVS triggers release of mtDNA which activates the NLRP3 inflammasome. Bacteria manipulate mitochondria during infection by either (A) secreting bacterial proteins or toxins, or (B) entering host cells via phagocytosis where mitochondria are recruited to the phagosome through toll-like receptor (TLR) signaling. Bacteria can either suppress or amplify mROS generation. The antimicrobial activity of mROS influences mtDNA “leakage”, which further amplifies mROS, and activation of the NLRP3 inflammasome. For both viral and bacterial infections, activation of the NLRP3 inflammasome triggers the release of IL-1β and IL-18. Release of these proinflammatory cytokines influences immune and inflammatory gene expression. Adapted from “Endocytosis and Exocytosis with Membrane Rupture (Layout)”, by BioRender.com. Retrieved from https://app.biorender.com/biorender-templates.

Figure 2

A Prospective Comparison of a Healthy Inflammatory Response and that in Kawasaki DiseaseProspective mechanisms of mitochondrial dysfunction and exaggerated activation of NLRP3 inflammasomes in KD upon infection compared to a healthy response. The healthy response is in blue, on the left-hand side of the figure. The KD response is in red, on the right-hand side of the diagram. Formation of the NLRP3 inflammasome complex occurs in the cytosol of monocytes/macrophages in the presence of PAMPs and/or DAMPs (i.e., cytosolic mROS and mtDNA). A healthy inflammatory response upon infection involves appropriate signaling from the mitochondria and activation of the NLRP3 inflammasome to clear the infection. In KD, damaged mitochondria release more mROS and mtDNA into the cytosol, which exaggerates activation of the NLRP3 inflammasome. This promotes NETosis and impairs immune cell functions. Adapted from “Suppression of Inflammasome by IRF4 and IRF8 is Critical for T Cell Priming”, by www.BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates .

Figure 3

Bidirectional Mito-Nuclear CrosstalkMitochondria and the nucleus communicate through retrograde (purple) and anterograde (blue) signaling pathways. This bidirectional crosstalk allows a cell to maintain homeostasis and adapt to various pressures. Retrograde (mitochondria-to-nucleus) communication influences the regulation of nuclear encoded mitochondrial proteins and expression of proinflammatory genes through altered concentration of metabolites, cytosolic mtDNA, and mROS. Anterograde signaling, as a response, can further influence the availability of mitochondrial derived metabolities needed for cell survival and disrupt mitochondrial oxidative efficiency.

Figure 4

Prospective Two-Hit Model of Mitochondrial Dysfunction in Kawasaki DiseaseSchematic representation of the perspective inflammatory response in a healthy state and in a Kawasaki diseased state, including the role of mitochondria in driving KD responses. (1) A mitochondrial SNP or haplogroup background results in abnormally proinflammatory mitochondria that are more likely to release mtDNA into the cytosol and produce ROS. These ROS oxidize cytosolic mtDNA and are recognized by circulating immune cells as DAMPs. Exposure to DAMPs activates the NLRP3 inflammasome, leading to proinflammatory cytokine release, such as IL-1β and IL-18. (2) Several viruses or bacteria manipulate mitochondria during infection. This could lead to a hyperimmune response and cytokine storm from previously damaged mitochondria (i.e., those prone to pyroptosis or impaired mitophagy). ROS and secreted cytokines further amplify this response in a feedback loop. Adapted from “Lipids and Proteins Involved in Lipid Uptake and Metabolism in Cardiac Lipotoxicity”, by BioRender.com. Retrieved from https://app.biorender.com/biorender-templates.

Figure 5

Mitochondrial Heteroplasmy and Disease ThresholdSchematic representation of mtDNA heteroplasmy and disease threshold. Blue mitochondria represent wild-type mtDNA, while red mitochondria represent mutant mtDNA. A cell may harbor all wild-type mtDNA, while others accumulate mutant mtDNA. The ratio of wild-type to mutant mtDNA can vary from cell-to-cell. When a pathogenic threshold is reached, a disease phenotype may emerge. The threshold depends on the pathogenicity of the mutation and bioenergetics the tissue. Cardiac tissue has high energy requirements, so a low mutant mtDNA may result in cellular dysfunction. Adapted from “mtDNA Heteroplasmy”, by www.BioRender.com. Retrieved from https://app.biorender.com/biorender-templates .