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Mitochondrial dynamics as a hub in the control of muscle inflammation

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Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular

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[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.

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[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.

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Tesis Doctorals - Departament - Bioquímica i Biomedicina Molecular

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Mitochondrial dynamics as a hub in the control of muscle inflammation