Related Experiment Video
Updated: Jul 17, 2025
Author Spotlight: New Insights into PBMC Mitochondrial Responses Using Fluorespirometry
Published on: May 24, 2024
Secretion of mitochondrial DNA via exosomes promotes inflammation in Behçet's syndrome
Hachiro Konaka1,2,3, Yasuhiro Kato1,2,4, Toru Hirano1,5
1Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Abstract:
Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase-1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin-D. Caspase-1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo. We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase-1 activation, leading to exosome-mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA-containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases.
Insights
Noxious stimuli cause mitochondrial DNA (mtDNA) release via pyroptosis. This mtDNA is secreted in exosomes, promoting inflammation and potentially exacerbating diseases like Behçet's syndrome.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Mitochondrial DNA (mtDNA) released into the cytoplasm can trigger inflammatory responses.
- Extracellular mtDNA contributes to sterile inflammation, but its secretion mechanism is unclear.
- Understanding mtDNA secretion is crucial for inflammatory disease research.
Purpose of the Study:
- To elucidate the mechanism of mitochondrial DNA secretion from cells.
- To investigate the role of exosome-mediated mtDNA secretion in inflammation.
- To explore the relevance of this pathway in human inflammatory disorders.
Main Methods:
- Induction of pyroptosis and caspase-1 activation in cells.
- Analysis of mitochondrial DNA localization and exosome formation.
- In vivo studies involving exosome biosynthesis inhibition.
- Isolation and analysis of monocytes from Behçet's syndrome patients.
Main Results:
- Pyroptotic cells secrete mitochondrial DNA encapsulated within exosomes.
- Caspase-1 activation, via gasdermin-D, mediates mtDNA release into the cytoplasm and subsequent exosome packaging.
- Inhibition of exosome biosynthesis reduced the inflammatory response.
- Monocytes from Behçet's syndrome patients exhibit enhanced caspase-1 activation and exosome-mediated mtDNA secretion.
Conclusions:
- Mitochondrial DNA-containing exosomes are a key mechanism for promoting inflammation.
- This exosome-mediated mtDNA secretion pathway contributes to the pathology of human inflammatory diseases like Behçet's syndrome.
- Targeting exosome biogenesis may offer therapeutic strategies for inflammatory conditions.
Related Concept Videos
01:45Mitochondrial Membranes
01:28The Inner Mitochondrial Membrane
02:59Animal Mitochondrial Genetics
01:37Mitochondria
01:19Translocation of Proteins into the Mitochondria
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
01:12Porin Insertion in the Outer Mitochondrial Membrane
Three models describe the assembly of porins by the SAM complex and their insertion into the outer membrane. Model 1 suggests that porins are assembled outside the SAM channel as the...