Related Experiment Video
Updated: Sep 12, 2025
Mouse Model of Oleic Acid-Induced Acute Respiratory Distress Syndrome
Published on: June 2, 2022
Effect of Regulating FUNDC1 Mitophagy-Mediated cGAS/STING Pathway in Oleic Acid-Induced Acute Lung Injury Model
Liangyu Mi1, Yuankai Zhou1, Wenyan Ding1
1State Key Laboratory of Complex Severe and Rare Disease, Department of Critical Care Medicine Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China.
Abstract:
Acute lung injury (ALI) involves inflammatory cytokines and chemokines, resulting in lung and multiple organ injuries. This study explored the mechanism of mitophagy and cGAS/STING pathway in oleic acid (OA)-induced ALI. Mice and pulmonary microvascular endothelial cells were divided into four groups: control group (Con), ALI group, FUNDC1 -/- control group (F-Con), and FUNDC1 -/- ALI group (F-ALI). After 24 h of modeling, proceed with tissue collection. Lung tissues were stained using hematoxylin eosin. Autophagosomes were observed by electron microscope and mtDNA was detected by qPCR. Western blot was used to analyze protein expression of pathways cGAS, STING, pTBK1, pIRF3, and pNF-κB. Serum IFN-β expression was detected by ELISA. Cellular morphological changes were observed using microscopy. LDH level, cGAS, and STING in endothelial cells were observed. Compared with control group, pathological changes in ALI group were significantly aggravated. Expressions of serum IFN-β, cGAS, STING, pTBK1, pIRF3, and pNF-κB in lung tissues of ALI mice were significantly higher than control group. After OA, the morphology of lung microvascular endothelial cells changed and LDH expression increased. After FUNDC1 gene was knocked out to inhibit mitophagy, autophagosomes were significantly reduced and mtDNA increased. Expressions of pathway proteins in lung tissues and cells of FUNDC1 -/- ALI group were higher than those of wild-type ALI group. Serum IFN-β expression also increased. Silencing FUNDC1 inhibits mitophagy. Subsequently, accumulated mtDNA activates cGAS/STING pathway, aggravating ALI pathological damage and inflammation, suggesting that mitophagy may provide protection in OA-induced ALI through cGAS/STING pathway.
Insights
Mitophagy, a cellular process, protects against acute lung injury (ALI). Inhibiting mitophagy in ALI exacerbates lung damage by activating the cGAS/STING pathway via accumulated mitochondrial DNA (mtDNA).
Area of Science:
- Cellular Biology
- Immunology
- Pathology
Background:
- Acute lung injury (ALI) is a critical condition characterized by inflammation and organ damage.
- The roles of mitophagy and the cGAS/STING pathway in ALI pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the involvement of mitophagy and the cGAS/STING pathway in oleic acid (OA)-induced ALI.
- To elucidate the protective mechanisms of mitophagy in ALI.
Main Methods:
- Utilized a mouse model of OA-induced ALI and pulmonary microvascular endothelial cells.
- Assessed lung injury using histology, electron microscopy, qPCR, Western blot, and ELISA.
- Manipulated FUNDC1 expression to inhibit mitophagy and observed downstream effects on the cGAS/STING pathway and cellular damage markers.
Main Results:
- OA-induced ALI led to significant lung pathological changes, increased inflammatory markers (IFN-β), and elevated cGAS/STING pathway activation.
- Inhibition of mitophagy by FUNDC1 knockout resulted in reduced autophagosomes, increased mtDNA accumulation, and exacerbated ALI.
- FUNDC1 deficiency aggravated ALI by activating the cGAS/STING pathway, indicated by increased pathway protein and serum IFN-β levels.
Conclusions:
- Mitophagy plays a protective role in OA-induced ALI.
- Accumulated mtDNA due to inhibited mitophagy activates the cGAS/STING pathway, worsening ALI.
- Targeting mitophagy may offer a therapeutic strategy for ALI.
