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

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.

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

“…Our study reveals that photon and proton irradiation induce a simultaneous accumulation of damaged mitochondria and cytoplasmic dsDNA and mtDNA at 6 days post-irradiation. This aligns with previous work of us 46 and others 47 , showing a correlation between the accumulation of elongated-damaged mitochondria and the upregulation of IFN-β following mtDNA leakage into the cytoplasm. The low levels of cGAS, however, suggest the involvement of other cytoplasmic nucleic acid sensors, such as ZBP1 48 .…”

Lysosomal uptake of mtDNA mitigates heteroplasmy

“…RAB5C physically interacts with the mitochondrial membrane proteins Mitofusin 1 and Mitofusin 2 and assists in endosomal approach and mtDNA transfer 9 .…”

“…Thus, RAB5, and in particular RAB5C, seems to participate in cargo selection. RAB5C physically interacts with the mitochondrial membrane proteins Mitofusin 1 and Mitofusin 2 and assists in endosomal approach and mtDNA transfer 9 . Similarly, upon mtDNA replication stress, mtDNA delivery to VPS35-RAB5 endosomes requires the mitochondrial membrane protein SAMM50 6 .…”

Implantable Epigallocatechin Gallate Sustained-Release Nanofibers for the Prevention of Immobilization-Induced Muscle Atrophy

“…2,3 Furthermore, when faced with injury, illness, or disease that is characterized by an inflammatory response, the release of a group of systemic mediators can intensify the consequences of skeletal muscular inactivity and speed up muscle atrophy. 4 However, in the early stage of muscle atrophy, many patients have no special symptoms and occasionally feel uncomfortable. Without intervention, especially postoperative limb immobilization, the muscle atrophy will be further aggravated, leading to deterioration of joint stability and secondary osteoarthritis.…”

“…The majority of people have lower muscle usage loss as a result of various diseases requiring bed rest or limb immobilization after surgery and mandatory lockdowns (such as the COVID-19 pandemic’s requirement that people stay at home). In addition, disorders that negatively influence mental health (such as depression) are frequent causes of muscle wasting because they result in a decline in total physical activity. , Furthermore, when faced with injury, illness, or disease that is characterized by an inflammatory response, the release of a group of systemic mediators can intensify the consequences of skeletal muscular inactivity and speed up muscle atrophy . However, in the early stage of muscle atrophy, many patients have no special symptoms and occasionally feel uncomfortable.…”