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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Marta Vilaseca

LAB HEAD: Antonio Zorzano

PROVIDER: PXD037935 | Pride | 2023-01-20

REPOSITORIES: Pride

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

Irazoki Andrea A Gordaliza-Alaguero Isabel I Frank Emma E Giakoumakis Nikolaos Nikiforos NN Seco Jordi J Palacín Manuel M Gumà Anna A Sylow Lykke L Sebastián David D Zorzano Antonio A

Nature communications 20230106 1

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 mi ...[more]

PMID: 36609505

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