Emerging evidence suggests that mitochondrial abnormalities contribute to immune dysregulation and organ damage in systemic lupus erythematosus (SLE). In a new study, targeting mitochondrial dysfunction using the drug idebenone improved clinical and immunological features of lupus-like disease in mice, highlighting idebenone as a promising new drug for SLE.

Credit: nobeastsofierce Science/Alamy Stock Photo

Idebenone is a coenzyme Q10 synthetic quinone analogue that has antioxidant properties. Notably, this drug is already approved in some countries for the treatment of other conditions associated with mitochondrial dysfunction (such as Duchenne muscular dystrophy).

“In two mouse models of SLE, we found that administration of idebenone reduced renal inflammation and renal function, attenuated systemic immune dysregulation in the innate and adaptive immune systems and improved mitochondrial metabolism,” states Mariana Kaplan, corresponding author on the study.

Treatment with idebenone improved the survival of the mice and was well tolerated. “Importantly, the use of idebenone was associated with improvements in endothelium-dependent vasorelaxation, suggesting that this drug could target lupus vasculopathy, a prominent feature in this disease,” explains Kaplan.

One mechanism by which mitochondrial dysfunction and aberrant production of mitochondrial reactive oxygen species (mROS) might contribute to SLE is by promoting the formation of neutrophil extracellular traps (NETs) and activation of the type I interferon pathway. Indeed, in neutrophils from mice with lupus or from patients with SLE, ex vivo treatment with idebenone inhibited spontaneous NET formation. Furthermore, in the mouse neutrophils, this treatment was associated with decreased mROS synthesis.

treatment with idebenone inhibited spontaneous NET formation

“We are continuing to investigate potential therapeutic targets that modify mitochondrial function and immunometabolism in SLE,” says Kaplan. “Our hope is to be able to identify the best compounds that could be tested in clinical trials in SLE in the future.”