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

Area of Science:

• Cellular Biology
• Immunology
• Muscle Physiology

Background:

• Mitochondrial dysfunction can cause sterile inflammation via DNA sensor activation.
• The role of mitochondrial dynamics in inflammation and muscle health is unclear.

Purpose of the Study:

• Investigate how mitochondrial morphology influences sterile inflammation.
• Determine the impact of mitochondrial dynamics on skeletal muscle fitness and inflammation.

Main Methods:

• Compared inflammatory responses to distinct mitochondrial morphologies.
• Examined mitochondria-endosome contacts involving Rab5C in TLR9 activation.
• Assessed skeletal muscle inflammation, atrophy, and performance in fragmented mitochondria models.

Main Results:

• Opposite mitochondrial shapes activate different DNA sensors (TLR9 or cGAS), leading to distinct inflammatory profiles.
• Mitochondria-endosome contacts mediated by Rab5C are crucial for TLR9 activation during fragmentation.
• Skeletal muscle fragmentation causes TLR9-dependent inflammation, atrophy, and reduced performance, which improves with anti-inflammatory treatment.

Conclusions:

• Mitochondrial dynamics are critical in preventing sterile inflammation, muscle atrophy, and performance decline.
• Targeting mitochondrial dynamics offers a potential therapeutic strategy for chronic inflammatory and mitochondrial disorders.