Mitochondrial dynamics as a hub in the control of muscle inflammation

[eng] Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA (mtDNA) recognition by intracellular DNA sensors. However, our understanding of the processes operating this activation is partial. Here we have analyzed the participation of mitochondrial dynamics in...

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Detalles Bibliográficos
Autor: Irazoqui Guimon, Andrea
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/186126
Acceso en línea:https://hdl.handle.net/2445/186126
http://hdl.handle.net/10803/674369
Access Level:acceso abierto
Palabra clave:Mitocondris
ADN mitocondrial
Inflamació
Múscul estriat
Mitochondria
Mitochondrial DNA
Inflammation
Striated muscle
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spelling Mitochondrial dynamics as a hub in the control of muscle inflammationIrazoqui Guimon, AndreaMitocondrisADN mitocondrialInflamacióMúscul estriatMitochondriaMitochondrial DNAInflammationStriated muscle[eng] Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA (mtDNA) recognition by intracellular DNA sensors. However, our understanding of the processes operating this activation is partial. Here we have analyzed the participation of mitochondrial dynamics in the control of inflammatory responses. We document that mitochondrial fragmentation causes NFκB-dependent inflammation, whereas mitochondrial elongation activates both NFκB and type I interferon (IFN) inflammatory responses in muscle cells. This differential response is a consequence of activation of the DNA sensors TLR9 or cGAS. Surprisingly, we also document that Mfn1 deficiency-induced inflammation is associated with an enhanced encounter of mitochondria with early endosomes, which requires the participation of the early endosomal protein Rab5C. Mfn1 ablation in mouse skeletal muscles promoted NFκB activation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which were improved or rescued upon chronic anti- inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in mitigating different inflammatory responses through mtDNA mislocation. We also demonstrate that muscle inflammation caused by mitochondrial fragmentation precedes the development of muscle atrophy and impaired physical performance. Therefore, we propose that inflammatory muscle disorders characterized by triggering of DNA sensors can be underpinned by therapeutic strategies promoting balanced mitochondrial dynamics.[spa] El objetivo principal del trabajo realizado en esta tesis es el de describir los mecanismos moleculares por los que alteraciones en la dinámica mitocondrial desencadenan inflamación en el músculo, así como el impacto fisiológico que esto puede causar. Este objetivo principal se divide en tres partes: 1. Descripción de las alteraciones en la dinámica mitocondrial que inducen inflamación y evaluación de las características moleculares comunes involucradas. 2. Caracterización de los mecanismos moleculares que relacionan la fragmentación mitocondrial inducida por la deficiencia de Mfn1 con la inflamación intracelular. 3. Evaluación del impacto de la depleción de Mfn1 en el desarrollo de la inflamación muscular y atrofia, así como la evaluación de la capacidad física.Universitat de BarcelonaZorzano Olarte, AntonioGumà i Garcia, Anna MariaUniversitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular2021info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/186126http://hdl.handle.net/10803/674369Tesis Doctorals - Departament - Bioquímica i Biomedicina Molecularreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Irazoqui Guimon, Andrea, 2022info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1861262026-05-27T06:46:51Z
dc.title.none.fl_str_mv Mitochondrial dynamics as a hub in the control of muscle inflammation
title Mitochondrial dynamics as a hub in the control of muscle inflammation
spellingShingle Mitochondrial dynamics as a hub in the control of muscle inflammation
Irazoqui Guimon, Andrea
Mitocondris
ADN mitocondrial
Inflamació
Múscul estriat
Mitochondria
Mitochondrial DNA
Inflammation
Striated muscle
title_short Mitochondrial dynamics as a hub in the control of muscle inflammation
title_full Mitochondrial dynamics as a hub in the control of muscle inflammation
title_fullStr Mitochondrial dynamics as a hub in the control of muscle inflammation
title_full_unstemmed Mitochondrial dynamics as a hub in the control of muscle inflammation
title_sort Mitochondrial dynamics as a hub in the control of muscle inflammation
dc.creator.none.fl_str_mv Irazoqui Guimon, Andrea
author Irazoqui Guimon, Andrea
author_facet Irazoqui Guimon, Andrea
author_role author
dc.contributor.none.fl_str_mv Zorzano Olarte, Antonio
Gumà i Garcia, Anna Maria
Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular
dc.subject.none.fl_str_mv Mitocondris
ADN mitocondrial
Inflamació
Múscul estriat
Mitochondria
Mitochondrial DNA
Inflammation
Striated muscle
topic Mitocondris
ADN mitocondrial
Inflamació
Múscul estriat
Mitochondria
Mitochondrial DNA
Inflammation
Striated muscle
description [eng] Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA (mtDNA) recognition by intracellular DNA sensors. However, our understanding of the processes operating this activation is partial. Here we have analyzed the participation of mitochondrial dynamics in the control of inflammatory responses. We document that mitochondrial fragmentation causes NFκB-dependent inflammation, whereas mitochondrial elongation activates both NFκB and type I interferon (IFN) inflammatory responses in muscle cells. This differential response is a consequence of activation of the DNA sensors TLR9 or cGAS. Surprisingly, we also document that Mfn1 deficiency-induced inflammation is associated with an enhanced encounter of mitochondria with early endosomes, which requires the participation of the early endosomal protein Rab5C. Mfn1 ablation in mouse skeletal muscles promoted NFκB activation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which were improved or rescued upon chronic anti- inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in mitigating different inflammatory responses through mtDNA mislocation. We also demonstrate that muscle inflammation caused by mitochondrial fragmentation precedes the development of muscle atrophy and impaired physical performance. Therefore, we propose that inflammatory muscle disorders characterized by triggering of DNA sensors can be underpinned by therapeutic strategies promoting balanced mitochondrial dynamics.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/186126
http://hdl.handle.net/10803/674369
url https://hdl.handle.net/2445/186126
http://hdl.handle.net/10803/674369
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Irazoqui Guimon, Andrea, 2022
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Irazoqui Guimon, Andrea, 2022
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Departament - 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 15,300719

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