Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation
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 oppo...
| Autores: | , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/192160 |
| Acceso en línea: | https://hdl.handle.net/2445/192160 |
| Access Level: | acceso abierto |
| Palabra clave: | ADN mitocondrial Mitocondris Malalties musculars ADN Envelliment Inflamació Mitochondrial DNA Mitochondria Muscular Diseases DNA Aging Inflammation |
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oai:recercat.cat:2445/192160 |
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Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation Irazoki, A. Gordaliza-Alaguero, Isabel Frank, Emma Giakoumakis, Nikolaos Nikiforos Seco, Jordi Palacín Prieto, Manuel Gumà i Garcia, Anna Maria Sylow, Lykke Sebastián Muñoz, David Zorzano Olarte, Antonio ADN mitocondrial Mitocondris Malalties musculars ADN Envelliment Inflamació Mitochondrial DNA Mitochondria Muscular Diseases DNA Aging Inflammation 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. Nature Publishing Group https://hdl.handle.net/2445/192160 |
| title |
Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation |
| spellingShingle |
Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation Irazoki, A. ADN mitocondrial Mitocondris Malalties musculars ADN Envelliment Inflamació Mitochondrial DNA Mitochondria Muscular Diseases DNA Aging Inflammation |
| title_short |
Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation |
| title_full |
Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation |
| title_fullStr |
Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation |
| title_full_unstemmed |
Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation |
| title_sort |
Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation |
| author |
Irazoki, A. |
| author_facet |
Irazoki, A. Gordaliza-Alaguero, Isabel Frank, Emma Giakoumakis, Nikolaos Nikiforos Seco, Jordi Palacín Prieto, Manuel Gumà i Garcia, Anna Maria Sylow, Lykke Sebastián Muñoz, David Zorzano Olarte, Antonio |
| author_role |
author |
| author2 |
Gordaliza-Alaguero, Isabel Frank, Emma Giakoumakis, Nikolaos Nikiforos Seco, Jordi Palacín Prieto, Manuel Gumà i Garcia, Anna Maria Sylow, Lykke Sebastián Muñoz, David Zorzano Olarte, Antonio |
| author2_role |
author author author author author author author author author |
| topic |
ADN mitocondrial Mitocondris Malalties musculars ADN Envelliment Inflamació Mitochondrial DNA Mitochondria Muscular Diseases DNA Aging Inflammation |
| topic_facet |
ADN mitocondrial Mitocondris Malalties musculars ADN Envelliment Inflamació Mitochondrial DNA Mitochondria Muscular Diseases DNA Aging Inflammation |
| description |
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. |
| publishDate |
2023 |
| format |
article |
| status_str |
publishedVersion |
| url |
https://hdl.handle.net/2445/192160 |
| eu_rights_str_mv |
openAccess |
| publisher |
Nature Publishing Group |
| institution |
Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| collection |
Recercat. Dipósit de la Recerca de Catalunya |
| reponame_str |
Recercat. Dipósit de la Recerca de Catalunya |
| instname_str |
Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| _version_ |
1878437694755831808 |
| publishDateSort |
2023 |
| author_browse |
Frank, Emma Giakoumakis, Nikolaos Nikiforos Gordaliza-Alaguero, Isabel Gumà i Garcia, Anna Maria Irazoki, A. Palacín Prieto, Manuel Sebastián Muñoz, David Seco, Jordi Sylow, Lykke Zorzano Olarte, Antonio |
| publisherStr |
Nature Publishing Group |
| score |
6,9303427 |