IFNγ causes mitochondrial dysfunction and oxidative stress in myositis.
Fiche publication
Date publication
juin 2024
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GENY Bernard
Tous les auteurs :
Abad C, Pinal-Fernandez I, Guillou C, Bourdenet G, Drouot L, Cosette P, Giannini M, Debrut L, Jean L, Bernard S, Genty D, Zoubairi R, Remy-Jouet I, Geny B, Boitard C, Mammen A, Meyer A, Boyer O
Lien Pubmed
Résumé
Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis.
Mots clés
Animals, Oxidative Stress, Interferon-gamma, metabolism, Myositis, metabolism, Humans, Female, Reactive Oxygen Species, metabolism, Mice, Mice, Inbred NOD, Mitochondria, metabolism, Muscle, Skeletal, metabolism, Disease Models, Animal, Mitochondria, Muscle, metabolism, Mice, Knockout, Myoblasts, metabolism
Référence
Nat Commun. 2024 06 26;15(1):5403