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MitoQ alleviates LPS-mediated acute lung injury through regulating Nrf2/Drp1 pathway
Lei Hou1, Jinyuan Zhang1, Yajing Liu1
1Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China.
Abstract:
Lipopolysaccharide (LPS) has been known to cause alveolar epithelial cell (AEC) apoptosis and barrier breakdown that characterize acute lung injury (ALI) and acute respiratory distress syndrome. We aimed to investigate whether mitoquinone (MitoQ), a mitochondria-targeted antioxidant, could alleviate LPS-induced AEC damage in ALI and its underlying mechanisms. In vitro studies in AEC A549 cell line, we noted that LPS could induce dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, AEC apoptosis and barrier breakdown, which could be reversed with MitoQ and mitochondrial division inhibitor 1 treatment. Moreover, the protective role of MitoQ was attenuated with Drp1 overexpression. Nuclear factor E2-related factor 2 (Nrf2) downregulation could block the effect of MitoQ by decreasing the expression of Nrf2 target genes in LPS-treated AEC, such as heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). Nrf2 gene knockdown in LPS-treated A549 cells prevented the protective effect of MitoQ from decreasing Drp1-mediated mitochondrial fission, AEC apoptosis and barrier breakdown. The lung protective effect of MitoQ by regulating the Drp1-mediated mitochondrial fission, AEC apoptosis and barrier breakdown was further confirmed in vivo with LPS-induced ALI mouse model. Additionally, the protective effect of MitoQ was inhibited by Nrf2 inhibitor ML385. We therefore conclude that MitoQ exerts ALI-protective effects by preventing Nrf2/Drp1-mediated mitochondrial fission, AEC apoptosis as well as barrier breakdown.
Insights
Mitoquinone (MitoQ) protects against acute lung injury (ALI) by preventing lipopolysaccharide-induced mitochondrial fission and cell damage. This protective effect involves the Nrf2/Drp1 pathway, highlighting MitoQ as a potential therapeutic for ALI.
Area of Science:
- Mitochondrial biology
- Cellular stress response
- Pulmonary medicine
Background:
- Lipopolysaccharide (LPS) induces acute lung injury (ALI) via alveolar epithelial cell (AEC) apoptosis and barrier dysfunction.
- Mitochondrial dynamics and oxidative stress are implicated in ALI pathogenesis.
Purpose of the Study:
- To investigate the protective effects of mitoquinone (MitoQ) against LPS-induced AEC damage in ALI.
- To elucidate the underlying molecular mechanisms involving mitochondrial fission and the Nrf2/Drp1 pathway.
Main Methods:
- In vitro studies using A549 cells treated with LPS, MitoQ, Drp1 inhibitors, and Nrf2 modulators.
- In vivo studies using an LPS-induced ALI mouse model.
- Assessment of AEC apoptosis, barrier integrity, mitochondrial fission (Drp1), and Nrf2 pathway activation.
Main Results:
- LPS induced Drp1-mediated mitochondrial fission, AEC apoptosis, and barrier breakdown.
- MitoQ treatment reversed LPS-induced damage, which was dependent on Nrf2 and attenuated by Drp1 overexpression.
- Nrf2 downregulation blocked MitoQ's protective effects.
- MitoQ demonstrated lung protective effects in vivo, inhibited by Nrf2 inhibition.
Conclusions:
- MitoQ exerts significant protective effects against ALI.
- The mechanism involves the regulation of Nrf2/Drp1-mediated mitochondrial fission, thereby preventing AEC apoptosis and barrier breakdown.
- MitoQ represents a promising therapeutic agent for ALI.
