Improved Mitochondrial Metabolism and Reduced Inflammation Following Attenuation of Murine Lupus With Coenzyme Q10 Analog Idebenone

Abstract

Objective A role for mitochondrial dysfunction has been proposed in the immune dysregulation and organ damage characteristic of systemic lupus erythematosus (SLE). Idebenone is a coenzyme Q10 synthetic quinone analog and an antioxidant that has been used in humans to treat diverse diseases in which mitochondrial function is impaired. This study was undertaken to assess whether idebenone ameliorates lupus in murine models. Methods Idebenone was administered orally to MRL/lpr mice at 2 different doses (1 gm/kg or 1.5 gm/kg idebenone‐containing diet) for 8 weeks. At peak disease activity, clinical, immunologic, and metabolic parameters were analyzed and compared to those in untreated mice (n = 10 per treatment group). Results were confirmed in the lupus‐prone NZM2328 mouse model. Results In MRL/lpr mice, idebenone‐treated mice showed a significant reduction in mortality incidence (P < 0.01 versus untreated mice), and the treatment attenuated several disease features, including glomerular inflammation and fibrosis (each P < 0.05 versus untreated mice), and improved renal function in association with decreased renal expression of interleukin‐17A (IL‐17A) and mature IL‐18. Levels of splenic proinflammatory cytokines and inflammasome‐related genes were significantly decreased (at least P < 0.05 and some with higher significance) in mice treated with idebenone, while no obvious drug toxicity was observed. Idebenone inhibited neutrophil extracellular trap formation in neutrophils from lupus‐prone mice (P < 0.05) and human patients with SLE. Idebenone also improved mitochondrial metabolism (30% increase in basal respiration and ATP production), reduced the extent of heart lipid peroxidation (by one‐half that of untreated mice), and significantly improved endothelium‐dependent vasorelaxation (P < 0.001). NZM2328 mice exposed to idebenone also displayed improvements in renal and systemic inflammation, reducing the kidney pathology score (P < 0.05), IgG/C3 deposition (P < 0.05), and the gene expression of interferon, proinflammatory, and inflammasome‐related genes (at least P < 0.05 and some with higher significance). Conclusion Idebenone ameliorates murine lupus disease activity and the severity of organ damage, supporting the hypothesis that agents that modulate mitochondrial biologic processes may have a therapeutic role in human SLE.

Low‐Density Neutrophils in Systemic Lupus Erythematosus

“…This cytotoxicity is dependent on NET formation and the externalization and activation of matrix metalloproteinases . In support of these findings, administration of a potent antioxidant and ROS inhibitor, idebenone, inhibits NET formation and improves endothelial function in the MRL/ lpr murine model of SLE . Collectively, these data suggest that LDNs contribute to the excess cardiovascular risk in SLE and that targeting mitochondrial dysfunction or LDNs directly may be a potential treatment strategy.…”

“…Enhanced NETosis also results in comparatively higher secretions of interleukin‐17 (IL‐17), an important cytokine associated with T cell activation, particularly in autoimmunity (Table ). The NETosis in SLE LDNs is, in part, due to an increase in mitochondrial ROS (mtROS) release (Figure and Table ). Importantly, mtROS production is sufficient for the generation of NETs even in the absence of functional NADPH oxidase .…”

Idebenone: When an antioxidant is not an antioxidant

“…A growing body of evidence suggests that idebenone reduces inflammation in a variety of test systems such as lupus [ 106 ], neuroinflammation [ 58 , 74 ], ulcerative colitis [ 37 ], sepsis [ 107 ], nano-toxicity [ 108 ], atherosclerosis [ 48 ] and drug-induced inflammation [ 109 ]. This effect cannot be explained by antioxidant activity or a normalisation of energy supply alone.…”

Systemic Lupus Erythematosus (SLE) Therapy: The Old and the New

“…Mitochondrial dysfunction recently emerged as a pivotal factor in the immune dysregulation and development of organ damage in SLE. Idebenone, a coenzyme Q10 synthetic quinone analog, has been found to ameliorate disease activity and the severity of organ damage, including glomerular inflammation and fibrosis in a murin model of SLE, suggesting a potential therapeutic role in humans [78]. Oxidative stress is increased in SLE, contributing to immune system dysregulation and comorbidities [79].…”