Rodriguez-Nuevo 2018 EMBO J

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Rodríguez-Nuevo A, Díaz-Ramos A, Noguera E, Díaz-Sáez F, Duran X, Muñoz JP, Romero M, Plana N, Sebastián D, Tezze C, Romanello V, Ribas F, Seco J, Planet E, Doctrow SR, González J, Borràs M, Liesa M, Palacín M, Vendrell J, Villarroya F, Sandri M, Shirihai O, Zorzano A (2018) Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency. EMBO J 37.

» PMID: 29632021

Rodriguez-Nuevo A, Diaz-Ramos A, Noguera E, Diaz-Saez F, Duran X, Munoz JP, Romero M, Plana N, Sebastián D, Tezze C, Romanello V, Ribas F, Seco J, Planet E, Doctrow SR, Gonzalez J, Borras M, Liesa M, Palacin M, Vendrell J, Villarroya F, Sandri M, Shirihai O, Zorzano A (2018) EMBO J

Abstract: 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.


Bioblast editor: Kandolf G O2k-Network Lab: ES Barcelona Zorzano A


Labels: MiParea: Respiration, mtDNA;mt-genetics, mt-Medicine 


Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 


Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: N, S, NS  HRR: Oxygraph-2k 

Labels, 2018-05