Mitochondrial activity is up-regulated in nonlesional atopic dermatitis and amenable to therapeutic intervention
Authors
Geraldine Leman, Petra Pavel, Martin Hermann, Debra Crumrine, Peter M. Elias, Deborah Minzaghi, Dominique Goudounèche, Natalia M. Roshardt Prieto, Maria Cavinato, Andrea Wanner, Stefan Blunder, Robert Gruber, Pidder Jansen-Dürr, Sandrine Dubrac
Institution
Medical University of Innsbruck
Country
Austria
Year
2022
Journal
Journal of Investigative Dermatology
Abstract
Previous work has shown increased expression of genes related to oxidative stress in nonlesional atopic dermatitis (ADNL) skin. Although mitochondria are key regulators of ROS production, their function in AD has never been investigated. Energy metabolism and the oxidative stress response were studied in keratinocytes (KCs) from patients with ADNL or healthy controls. Moreover, ADNL human epidermal equivalents were treated with tigecycline or MitoQ. We found that pyruvate and glucose were used as energy substrates by ADNL KCs. Increased mitochondrial oxidation of (very) long-chain fatty acids, associated with enhanced complexes I and II activities, was observed in ADNL KCs. Metabolomic analysis revealed increased tricarboxylic acid cycle turnover. Increased aerobic metabolism generated oxidative stress in ADNL KCs. ADNL human epidermal equivalents displayed increased mitochondrial function and an enhanced oxidative stress response compared with controls. Treatment of ADNL human epidermal equivalents with tigecycline or MitoQ largely corrected the AD profile, including high p-65 NF-κB, abnormal lamellar bodies, and cellular damage. Furthermore, we found that glycolysis supports but does not supersede mitochondrial metabolism in ADNL KCs. Thus, aerobic metabolism predominates in ADNL but leads to oxidative stress. Therefore, mitochondria could be a reservoir of potential therapeutic targets in atopic dermatitis.