Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency
| Autor: | Javier González, Susan R. Doctrow, Angels Díaz-Ramos, Antonio Zorzano, Aida Rodríguez-Nuevo, Manuel Palacín, Xavier Duran, M. Romero, Eduard Noguera, Joan Vendrell, Orian S. Shirihai, M. Borràs, Caterina Tezze, David Sebastián, Juan Pablo Muñoz, Francesc Villarroya, Marco Sandri, Francesc Ribas, Francisco Díaz-Sáez, Marc Liesa, Natàlia Plana, Vanina Romanello, Jordi Seco, Evarist Planet |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Programmed cell death endocrine system Inflammation Apoptosis Mitochondrion Biology Systemic inflammation DNA Mitochondrial General Biochemistry Genetics and Molecular Biology GTP Phosphohydrolases 03 medical and health sciences chemistry.chemical_compound Necrosis 0302 clinical medicine Muscular Diseases medicine Myocyte Animals Regeneration Inner mitochondrial membrane Muscle Skeletal Molecular Biology Sodium salicylate Cells Cultured Mice Knockout General Immunology and Microbiology General Neuroscience Articles eye diseases Cell biology 030104 developmental biology chemistry Toll-Like Receptor 9 Cytokines Female medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | The EMBO journal. 37(10) |
| ISSN: | 1460-2075 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text