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Secreted mitochondrial aspartyl-tRNA synthetase (DARS2) regulates TNFα signaling
Benjamin S Johnson1, Alex Cornwell1, Daniela Farkas1
1Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio, USA.
Physiological Reports
|November 11, 2025
Summary
Mitochondrial Aspartyl-tRNA Synthetase (DARS2) is secreted from airway cells upon TNFα stimulation. This released DARS2 induces an M1-like phenotype in macrophages, highlighting a novel paracrine signaling pathway.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Aminoacyl-tRNA Synthetases (aaRS) regulate cytokine signaling.
- Cytoplasmic aaRS members are secreted to modulate responses.
- Mitochondrial aaRS release and its role in paracrine signaling remain largely undescribed.
Purpose of the Study:
- To investigate the release of mitochondrial Aspartyl-tRNA Synthetase (DARS2) from airway epithelia.
- To determine the role of secreted DARS2 in macrophage activation.
- To elucidate the molecular pathways governing DARS2 secretion.
Main Methods:
- Utilized BEAS-2B cells to study DARS2 release in response to cytokines like TNFα.
- Employed adoptive media transfer to assess DARS2's paracrine signaling effects on THP1 cells.
- Used blocking antibodies, chemical inhibitors, and siRNA to identify secretion pathways.
Main Results:
- Identified DARS2 as the first mitochondrial aaRS released from airway epithelia in response to TNFα.
- Demonstrated that secreted DARS2 binds to macrophages, is internalized, and induces an M1-like phenotype.
- Showed DARS2 release is partially dependent on TNFα-receptor 1 and requires the endosomal sorting complex for extracellular transport.
Conclusions:
- DARS2 is a novel secreted mitochondrial protein involved in intercellular communication.
- TNFα-induced DARS2 secretion from airway cells influences macrophage polarization.
- This pathway represents a new mechanism in immune regulation and inflammation.
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