PMID- 33539948 OWN - NLM STAT- MEDLINE DCOM- 20210628 LR - 20210628 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 165 DP - 2021 Mar TI - MitoQ alleviates LPS-mediated acute lung injury through regulating Nrf2/Drp1 pathway. PG - 219-228 LID - S0891-5849(21)00062-9 [pii] LID - 10.1016/j.freeradbiomed.2021.01.045 [doi] AB - 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. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Hou, Lei AU - Hou L AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Zhang, Jinyuan AU - Zhang J AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Liu, Yajing AU - Liu Y AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Fang, Hongwei AU - Fang H AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Liao, Lijun AU - Liao L AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Wang, Zhankui AU - Wang Z AD - Department of Orthopedics, The First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China. FAU - Yuan, Jie AU - Yuan J AD - Department of Pain, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China. FAU - Wang, Xuebin AU - Wang X AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Sun, Jixiong AU - Sun J AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Tang, Bing AU - Tang B AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Chen, Hongfei AU - Chen H AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Ye, Pengcheng AU - Ye P AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Ding, Zhenmin AU - Ding Z AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. FAU - Lu, Huihong AU - Lu H AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. Electronic address: luhhong@hotmail.com. FAU - Wang, Yinglin AU - Wang Y AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. Electronic address: 13907553360@163.com. FAU - Wang, Xiangrui AU - Wang X AD - Department of Anesthesiology and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong, Shanghai, 200120, China. Electronic address: xiangruiwang2016@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210201 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Lipopolysaccharides) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Organophosphorus Compounds) RN - 1339-63-5 (Ubiquinone) RN - 47BYS17IY0 (mitoquinone) RN - EC 3.6.5.5 (Dynamins) SB - IM MH - *Acute Lung Injury/chemically induced/drug therapy/genetics MH - Animals MH - Dynamins MH - Lipopolysaccharides/toxicity MH - Mice MH - *NF-E2-Related Factor 2/genetics/metabolism MH - Organophosphorus Compounds MH - Signal Transduction MH - Ubiquinone/analogs & derivatives OTO - NOTNLM OT - Apoptosis OT - Drp1 OT - LPS OT - MitoQ OT - Mitochondrial fission EDAT- 2021/02/05 06:00 MHDA- 2021/06/29 06:00 CRDT- 2021/02/04 20:13 PHST- 2020/12/11 00:00 [received] PHST- 2021/01/18 00:00 [revised] PHST- 2021/01/23 00:00 [accepted] PHST- 2021/02/05 06:00 [pubmed] PHST- 2021/06/29 06:00 [medline] PHST- 2021/02/04 20:13 [entrez] AID - S0891-5849(21)00062-9 [pii] AID - 10.1016/j.freeradbiomed.2021.01.045 [doi] PST - ppublish SO - Free Radic Biol Med. 2021 Mar;165:219-228. doi: 10.1016/j.freeradbiomed.2021.01.045. Epub 2021 Feb 1.