Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency

• Published in: The EMBO journal Vol. 37; no. 10
• Main Authors: Rodríguez‐Nuevo, Aida, Díaz‐Ramos, Angels, Noguera, Eduard, Díaz‐Sáez, Francisco, Duran, Xavier, Muñoz, Juan Pablo, Romero, Montserrat, Plana, Natàlia, Sebastián, David, Tezze, Caterina, Romanello, Vanina, Ribas, Francesc, Seco, Jordi, Planet, Evarist, Doctrow, Susan R, González, Javier, Borràs, Miquel, Liesa, Marc, Palacín, Manuel, Vendrell, Joan, Villarroya, Francesc, Sandri, Marco, Shirihai, Orian, Zorzano, Antonio
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.05.2018; Springer Nature B.V; John Wiley and Sons Inc
• Subjects: Ablation; Animals; Apoptosis; Cell activation; Cell death; Cells, Cultured; Cristae; Cytokines - metabolism; Deoxyribonucleic acid; DNA; DNA, Mitochondrial - genetics; EMBO07; EMBO19; EMBO21; endosome; Female; Gene expression; Genes; GTP Phosphohydrolases - physiology; Impairment; Infiltration; Inflammation; Inflammation - etiology; Inflammation - metabolism; Inflammation - pathology; Inflammatory diseases; Macrophages; Male; Membrane fusion; Mice, Knockout; Mitochondria; Mitochondrial DNA; mitochondrial dynamics; Morphogenesis; muscle disease; Muscle, Skeletal - immunology; Muscle, Skeletal - pathology; Muscles; Muscular Diseases - etiology; Muscular Diseases - metabolism; Muscular Diseases - pathology; Musculoskeletal diseases; Musculoskeletal system; Myopathy; Necrosis; Regeneration; Salicylic acid; Skeletal muscle; Sodium; Sodium salicylate; Sodium salicylates; systemic inflammation; TLR9 protein; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - metabolism; Toll-like receptors; systemic inflammation; endosome; muscle disease; mitochondrial dynamics
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.201796553

Opa1 participates in inner mitochondrial membrane fusion and cristae morphogenesis. Here, we show that muscle‐specific Opa1 ablation causes reduced muscle fiber size, dysfunctional mitochondria, enhanced Fgf21, and muscle inflammation characterized by NF‐κB activation, and enhanced expression of pro‐inflammatory genes. Chronic sodium salicylate treatment ameliorated muscle alterations and reduced the muscle expression of Fgf21. Muscle inflammation was an early event during the progression of the disease and occurred before macrophage infiltration, indicating that it is a primary response to Opa1 deficiency. Moreover, Opa1 repression in muscle cells also resulted in NF‐κB activation and inflammation in the absence of necrosis and/or apoptosis, thereby revealing that the activation is a cell‐autonomous process and independent of cell death. The effects of Opa1 deficiency on the expression NF‐κB target genes and inflammation were absent upon mitochondrial DNA depletion. Under Opa1 deficiency, blockage or repression of TLR9 prevented NF‐κB activation and inflammation. Taken together, our results reveal that Opa1 deficiency in muscle causes initial mitochondrial alterations that lead to TLR9 activation, and inflammation, which contributes to enhanced Fgf21 expression and to growth impairment. Synopsis Mitochondrial DNA stress caused by Opa1 deficiency in skeletal muscle leads to inflammation via TLR9 activation, which contributes to enhanced Fgf21 expression and systemic growth impairment. Skeletal muscle‐specific Opa1 ablation causes mitochondrial inflammatory myopathy. Opa1 deficiency results in reduced muscle mass, mitochondrial dysfunction and enhanced Fgf21 expression. Opa1 deficiency‐dependent inflammation results in severe growth defects. Inflammation is a primary cell‐autonomous response of muscle cells to Opa1 deficiency, leading to NF‐κB activation. Opa1 deficiency activates TLR9 by a mechanism that requires mitochondrial DNA. Graphical Abstract Mitochondrial DNA stress caused by Opa1 deficiency in skeletal muscle leads to inflammation via TLR9 activation, which contributes to enhanced Fgf21 expression and systemic growth impairment.