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Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency.

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-?B 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-?B 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-?B target genes and inflammation were absent upon mitochondrial DNA depletion. Under Opa1 deficiency, blockage or repression of TLR9 prevented NF-?B 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.

SUBMITTER: Rodriguez-Nuevo A

PROVIDER: S-EPMC5978453 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency.

Rodríguez-Nuevo Aida A Díaz-Ramos Angels A Noguera Eduard E Díaz-Sáez Francisco F Duran Xavier X Muñoz Juan Pablo JP Romero Montserrat M Plana Natàlia N Sebastián David D Tezze Caterina C Romanello Vanina V Ribas Francesc F Seco Jordi J Planet Evarist E Doctrow Susan R SR González Javier J Borràs Miquel M Liesa Marc M Palacín Manuel M Vendrell Joan J Villarroya Francesc F Sandri Marco M Shirihai Orian O Zorzano Antonio A

The EMBO journal 20180409 10

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 ...[more]

PMID: 29632021

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Dataset Information

Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency.

Publications

Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency.

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