Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation

Andrea Irazoki, Isabel Gordaliza-Alaguero, Emma Frank, Nikolaos Nikiforos Giakoumakis, Jordi Seco, Manuel Palacín, Anna Gumà, Lykke Sylow, David Sebastián () and Antonio Zorzano ()
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Andrea Irazoki: The Barcelona Institute of Science and Technology
Isabel Gordaliza-Alaguero: The Barcelona Institute of Science and Technology
Emma Frank: University of Copenhagen
Nikolaos Nikiforos Giakoumakis: The Barcelona Institute of Science and Technology
Jordi Seco: The Barcelona Institute of Science and Technology
Manuel Palacín: The Barcelona Institute of Science and Technology
Anna Gumà: Universitat de Barcelona
Lykke Sylow: University of Copenhagen
David Sebastián: University of Barcelona
Antonio Zorzano: The Barcelona Institute of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35732-1

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DOI: 10.1038/s41467-022-35732-1

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