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2023-01-06

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cc-by (c) Irazoki, A. et al., 2023
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/192160

Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation

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https://doi.org/10.1038/s41467-022-35732-1

Abstract

Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA (mtDNA) recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics mitigating such processes and their impact on muscle fitness remain unaddressed. Here we report that opposite mitochondrial morphologies induce distinct inflammatory signatures, caused by differential activation of DNA sensors TLR9 or cGAS. In the context of mitochondrial fragmentation, we demonstrate that mitochondria-endosome contacts mediated by the endosomal protein Rab5C are required in TLR9 activation in cells. Skeletal muscle mitochondrial fragmentation promotes TLR9-dependent inflammation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which improved upon chronic anti-inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in preventing sterile inflammatory responses, which precede the development of muscle atrophy and impaired physical performance. Thus, we propose the targeting of mitochondrial dynamics as an approach to treating disorders characterized by chronic inflammation and mitochondrial dysfunction.

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ADN mitocondrial, Mitocondris, Malalties musculars, ADN, Envelliment, Inflamació

Subject (English)

Mitochondrial DNA, Mitochondria, Muscular Diseases, DNA, Aging, Inflammation

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Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (Bioquímica i Fisiologia)

Citation

IRAZOKI, A., et al. Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation. Nature Communications. 2023. Vol. 14 (1), num. 108, pags. 1-19. ISSN 2041-1723. [consulted: 9 of August of 2026]. Available at: https://hdl.handle.net/2445/192160

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