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...

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Authors: 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
Format: article
Status:Published version
Publication Date:2023
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/192160
Online Access:https://hdl.handle.net/2445/192160
Access Level:Open access
Keyword:ADN mitocondrial
Mitocondris
Malalties musculars
ADN
Envelliment
Inflamació
Mitochondrial DNA
Mitochondria
Muscular Diseases
DNA
Aging
Inflammation
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oai_identifier_str oai:diposit.ub.edu:2445/192160
network_acronym_str ES
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repository_id_str
spelling Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocationIrazoki, A.Gordaliza-Alaguero, IsabelFrank, EmmaGiakoumakis, Nikolaos NikiforosSeco, JordiPalacín Prieto, ManuelGumà i Garcia, Anna MariaSylow, LykkeSebastián Muñoz, DavidZorzano Olarte, AntonioADN mitocondrialMitocondrisMalalties muscularsADNEnvellimentInflamacióMitochondrial DNAMitochondriaMuscular DiseasesDNAAgingInflammationSome 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 Group2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/192160Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/s41467-022-35732-1Nature Communications, 2023, vol. 14 (1), num. 108, p. 1-19https://doi.org/10.1038/s41467-022-35732-1cc-by (c) Irazoki, A. et al., 2023https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1921602026-05-27T06:46:51Z
dc.title.none.fl_str_mv Dysruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation
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
dc.creator.none.fl_str_mv 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 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
dc.subject.none.fl_str_mv ADN mitocondrial
Mitocondris
Malalties musculars
ADN
Envelliment
Inflamació
Mitochondrial DNA
Mitochondria
Muscular Diseases
DNA
Aging
Inflammation
topic 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
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/192160
url https://hdl.handle.net/2445/192160
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41467-022-35732-1
Nature Communications, 2023, vol. 14 (1), num. 108, p. 1-19
https://doi.org/10.1038/s41467-022-35732-1
dc.rights.none.fl_str_mv cc-by (c) Irazoki, A. et al., 2023
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Irazoki, A. et al., 2023
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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