Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis

Abstract

Control of excessive mitochondrial oxidative stress could provide new targets for both preventive and therapeutic interventions in the treatment of chronic inflammation or any pathology that develops under an inflammatory scenario, such as rheumatoid arthritis (RA). Increasing evidence has demonstrated the role of mitochondrial alterations in autoimmune diseases mainly due to the interplay between metabolism and innate immunity, but also in the modulation of inflammatory response of resident cells, such as synoviocytes. Thus, mitochondrial dysfunction derived from several danger signals could activate tricarboxylic acid (TCA) disruption, thereby favoring a vicious cycle of oxidative/mitochondrial stress. Mitochondrial dysfunction can act through modulating innate immunity via redox-sensitive inflammatory pathways or direct activation of the inflammasome. Besides, mitochondria also have a central role in regulating cell death, which is deeply altered in RA. Additionally, multiple evidence suggests that pathological processes in RA can be shaped by epigenetic mechanisms and that in turn, mitochondria are involved in epigenetic regulation. Finally, we will discuss about the involvement of some dietary components in the onset and progression of RA.

Keywords: cell death; diet; epigenetic; inflammation; metabolism; mitochondria; oxidative stress; rheumatoid arthritis.

Figure 1

Theoretical model for the multidirectional interplays between mitochondrial oxidative stress, metabolic status, inflammation and cell death in RA. Mitochondria play essential roles at the crossroads of metabolism and innate immunity [54]. Thus, mitochondrial dysfunction derived from several danger signals could activate TCA disruption and thereby favoring a vicious cycle of oxidative/mitochondrial stress. In fact, oxidative damage in synovial tissue is associated with in vivo hypoxic status, high lactate and low glucose levels [3]. Mitochondrial dysfunction can act through modulating innate immunity via redox-sensitive inflammatory pathways (i.e., NF-κB) or direct activation of the inflammasome. Inflammasome activation and NF-κB pathway could work together to activate inflammatory cytokines, thereby leading to overstimulation of the inflammatory response. On the other hand, mitochondria also have a central position in regulating cell death. In this sense, the two main regulated cell death pathways, apoptosis and autophagy, cooperate in a balanced interaction that promotes cell survival or cell death. Additionally, NF-κB could restrict inflammasome activation via elimination of damaged mitochondria through p-62-dependent clearance of damaged mitochondria as well as autophagy modulate NF-κB activation [135]. Additionally, multiple evidence suggests that pathological processes in RA can be shaped by epigenetic mechanisms and that mitochondria are involved in epigenetic regulation [241]. Natural bioactive agents of a healthy diet could protect mitochondria and inhibit the overactivation of mitochondrial oxidative stress and the associated inflammatory response that define RA.