Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation
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Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics in 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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 108 |
| Tidsskrift | Nature Communications |
| Vol/bind | 14 |
| Udgave nummer | 1 |
| Antal sider | 19 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
We thank the IRB Barcelona Histopathology, Advanced Digital Microscopy and Functional Genomics Facilities, and the Flow Cytometry Unit at the CCiTUB, University of Barcelona. We also thank Yolanda Muela and Lidia Delgado from the Cryo-Microscopy Unit at the CCiTUB, Irene Gómez, Laura Isabel Alcaide, and Rosa Balmaseda from the Animal Facility at the PCB, and Katharina Stohlmann for technical assistance. We thank the Mass spectrometry and Proteomics facility from the IRB Barcelona. A.I. was the recipient of a fellowship from the University of Barcelona, Spain. This study was supported by research grants from MICINN (PID2019-106209RB-I00), the Generalitat de Catalunya (Grant 2017SGR1015), CIBERDEM (‘Instituto de Salud Carlos III’), the Fundación Ramon Areces (CIVP18A3942), the Fundación BBVA, the Fundació Marató de TV3 (20132330), EFSD, AFM Téléthon and Novo Nordisk Foundation (NNF18OC0032082, NNF16OC0023418, NNF20OC0063577). A.Z. is a recipient of an ICREA “Academia” Award (Generalitat de Catalunya). We gratefully acknowledge institutional funding from MINECO through the Centers of Excellence Severo Ochoa Award, and from the CERCA Programe run by the Generalitat de Catalunya.
Funding Information:
We thank the IRB Barcelona Histopathology, Advanced Digital Microscopy and Functional Genomics Facilities, and the Flow Cytometry Unit at the CCiTUB, University of Barcelona. We also thank Yolanda Muela and Lidia Delgado from the Cryo-Microscopy Unit at the CCiTUB, Irene Gómez, Laura Isabel Alcaide, and Rosa Balmaseda from the Animal Facility at the PCB, and Katharina Stohlmann for technical assistance. We thank the Mass spectrometry and Proteomics facility from the IRB Barcelona. A.I. was the recipient of a fellowship from the University of Barcelona, Spain. This study was supported by research grants from MICINN (PID2019-106209RB-I00), the Generalitat de Catalunya (Grant 2017SGR1015), CIBERDEM (‘Instituto de Salud Carlos III’), the Fundación Ramon Areces (CIVP18A3942), the Fundación BBVA, the Fundació Marató de TV3 (20132330), EFSD, AFM Téléthon and Novo Nordisk Foundation (NNF18OC0032082, NNF16OC0023418, NNF20OC0063577). A.Z. is a recipient of an ICREA “Academia” Award (Generalitat de Catalunya). We gratefully acknowledge institutional funding from MINECO through the Centers of Excellence Severo Ochoa Award, and from the CERCA Programe run by the Generalitat de Catalunya.
Publisher Copyright:
© 2023, The Author(s).
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