Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis

Abstract

Mitochondria are major energy-producing organelles that have central roles in cellular metabolism. They also act as important signalling hubs, and their dynamic regulation in response to stress signals helps to dictate the stress response of the cell. Rheumatoid arthritis is an inflammatory and autoimmune disease with high prevalence and complex aetiology. Mitochondrial activity affects differentiation, activation and survival of immune and non-immune cells that contribute to the pathogenesis of this disease. This review outlines what is known about the role of mitochondria in rheumatoid arthritis pathogenesis, and how current and future therapeutic strategies can function through modulation of mitochondrial activity. We also highlight areas of this topic that warrant further study. As producers of energy and of metabolites such as succinate and citrate, mitochondria help to shape the inflammatory phenotype of leukocytes during disease. Mitochondrial components can directly stimulate immune receptors by acting as damage-associated molecular patterns, which could represent an initiating factor for the development of sterile inflammation. Mitochondria are also an important source of intracellular reactive oxygen species, and facilitate the activation of the NLRP3 inflammasome, which produces cytokines linked to disease symptoms in rheumatoid arthritis. The fact that mitochondria contain their own genetic material renders them susceptible to mutation, which can propagate their dysfunction and immunostimulatory potential. Several drugs currently used for the treatment of rheumatoid arthritis regulate mitochondrial function either directly or indirectly. These actions contribute to their immunomodulatory functions, but can also lead to adverse effects. Metabolic and mitochondrial pathways are attractive targets for future anti-rheumatic drugs, however many questions still remain about the precise role of mitochondrial activity in different cell types in rheumatoid arthritis.

Keywords: DAMP; DMARD (disease modifying anti-rheumatic drug); NLRP3; metabolism; mitochondria; oxidative phosphorylation; rheumatoid arthritis.

Figure 1

Metabolic phenotype of different cell types in rheumatoid arthritis. ROS, reactive oxygen species; MAM, mitochondria-associated membrane.

Figure 2

Synovial tissue macrophage subpopulations display distinct metabolic gene expression signatures. Data from Alivernini et al. (39). (A) Heatmap of synovial tissue macrophage single cell RNA sequencing data displaying differential expression of metabolism-associated genes across macrophage subpopulations (clusters). Detailed information on the characterisation and function of different clusters and their contribution to different disease outcome groups can be found in Alivernini et al. (39). (B) Pathway schematic of the data from (A). Genes upregulated in at least one cluster of pro-inflammatory macrophages are displayed in red, and genes upregulated in at least one cluster of pro-resolving macrophages are displayed in blue. STM, synovial tissue macrophage; PPP, pentose phosphate pathway; ETC, electron transport chain.

Figure 3

Mitochondrial regulation of NLRP3 inflammasome activation and mitochondrial DAMP activity. The NLRP3 inflammasome is activated by signals including mitochondrial reactive oxygen species (ROS), oxidised mitochondrial DNA (ox-mtDNA) and potassium efflux through the ATP-gated channel P2X7. Components of the inflammasome localise to mitochondrial and ER membranes upon activation, where they associate with MAVS, Mfn 2 and cardiolipin in the outer mitochondria membrane. Oligomerised NLRP3 and its adapter protein ASC recruit and activate caspase-1, which cleaves gasdermin D and interleukin-1 family cytokines into their active forms. Ox-mtDNA also exhibits DAMP activity by stimulating other pattern recognition receptors including the endosomal toll-like receptor TLR9.