Nrf2 attenuates ferroptosis-mediated IIR-ALI by modulating TERT and SLC7A11

被引:150
作者
Dong, Hui [1 ]
Xia, Yangyang [1 ]
Jin, Shanliang [1 ]
Xue, Chaofan [2 ]
Wang, Yanjun [1 ]
Hu, Rong [1 ]
Jiang, Hong [1 ]
机构
[1] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Ctr Specialty Strategy Res, Sch Med,China Hosp,Dev Inst, Shanghai, Peoples R China
[2] Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai, Peoples R China
基金
上海市自然科学基金; 中国国家自然科学基金;
关键词
INTESTINAL ISCHEMIA-REPERFUSION; ACUTE LUNG INJURY; CELL-DEATH; PROTECTS; ISCHEMIA/REPERFUSION; INFLAMMATION; FERROPORTIN; ACTIVATION; PATHWAY; LIVER;
D O I
10.1038/s41419-021-04307-1
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Acute lung injury (ALI) carries a mortality rate of similar to 50% and is a hot topic in the world of critical illness research. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical modulator of intracellular oxidative homeostasis and serves as an antioxidant. The Nrf2-related anti-oxidative stress is strongly associated with ferroptosis suppression. Meanwhile, telomerase reverse transcriptase (TERT), the catalytic portion of the telomerase protein, is reported to travel to the mitochondria to alleviate ROS. In our study, we found that TERT was significantly reduced in lung tissue of Nrf2(-/-) mice in the model of intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI). In addition, MDA levels showed marked increase, whereas GSH and GPX4 levels fell drastically in ALI models. Moreover, typical-related structural changes were observed in the type II alveolar epithelial cells in the IIR model. We further employed the scanning transmission X-ray microscopy (STXM) to examine Fe levels and distribution within cells. Based on our observations, massive aggregates of Fe were found in the MLE-12 cells upon OGD/R (oxygen and glucose deprivation/reperfusion) induction. Additionally, Nrf2 silencing dramatically reduced TERT and SLC7A11 levels, and further exacerbated cellular injuries. In contrast, TERT-overexpressing cells exhibited marked elevation in SLC7A11 levels and thereby inhibited ferroptosis. Collectively, these data suggest that Nrf2 can negatively regulate ferroptosis via modulation of TERT and SLC7A11 levels. The conclusion from this study brings insight into new candidates that can be targeted in future IIR-ALI therapy.
引用
收藏
页数:10
相关论文
共 35 条
[1]   Non-transferrin bound iron: A key role in iron overload and iron toxicity [J].
Brissot, Pierre ;
Ropert, Martine ;
Le Lan, Caroline ;
Loreal, Olivier .
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 2012, 1820 (03) :403-410
[2]   Lung microvascular permeability and neutrophil recruitment are differently regulated by nitric oxide in a rat model of intestinal ischemia-reperfusion [J].
Cavriani, G ;
Oliveira, RM ;
Trezena, AG ;
da Silva, ZL ;
Domingos, HV ;
de Arruda, MJC ;
Jancar, S ;
de Lima, WT .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2004, 494 (2-3) :241-249
[3]   NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression [J].
Chen, Delin ;
Tavana, Omid ;
Chu, Bo ;
Erber, Luke ;
Chen, Yue ;
Baer, Richard ;
Gu, Wei .
MOLECULAR CELL, 2017, 68 (01) :224-+
[4]   Regulated necrosis: disease relevance and therapeutic opportunities [J].
Conrad, Marcus ;
Angeli, Jose Pedro Friedmann ;
Vandenabeele, Peter ;
Stockwell, Brent R. .
NATURE REVIEWS DRUG DISCOVERY, 2016, 15 (05) :348-366
[5]   Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death [J].
Dixon, Scott J. ;
Lemberg, Kathryn M. ;
Lamprecht, Michael R. ;
Skouta, Rachid ;
Zaitsev, Eleina M. ;
Gleason, Caroline E. ;
Patel, Darpan N. ;
Bauer, Andras J. ;
Cantley, Alexandra M. ;
Yang, Wan Seok ;
Morrison, Barclay, III ;
Stockwell, Brent R. .
CELL, 2012, 149 (05) :1060-1072
[6]   NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis [J].
Dodson, Matthew ;
Castro-Portuguez, Raul ;
Zhang, Donna D. .
REDOX BIOLOGY, 2019, 23
[7]   Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1 (vol 12, pg 12948, 2020) [J].
Dong, Hui ;
Qiang, Zhuanzhuan ;
Chai, Dongdong ;
Peng, Jiali ;
Xia, Yangyang ;
Hu, Rong ;
Jiang, Hong .
AGING-US, 2023, 15 (19) :10811-10812
[8]   Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis [J].
Fan, Z. ;
Wirth, A-K ;
Chen, D. ;
Wruck, C. J. ;
Rauh, M. ;
Buchfelder, M. ;
Savaskan, N. .
ONCOGENESIS, 2017, 6 :e371-e371
[9]   Estradiol mediates the long-lasting lung inflammation induced by intestinal ischemia and reperfusion [J].
Fantozzi, Evelyn Thais ;
Breithaupt-Faloppa, Ana Cristina ;
Ricardo-da-Silva, Fernanda Yamamoto ;
Rodrigues-Garbin, Sara ;
Romero, Daniel Cancelli ;
Rodrigues, Adriana da Silva ;
Riffo-Vasquez, Yanira ;
Tavares-de-Lima, Wothan .
JOURNAL OF SURGICAL RESEARCH, 2018, 221 :1-7
[10]   Oncogenic functions of the transcription factor Nrf2 [J].
Ganan-Gomez, Irene ;
Wei, Yue ;
Yang, Hui ;
Carmen Boyano-Adanez, Maria ;
Garcia-Manero, Guillermo .
FREE RADICAL BIOLOGY AND MEDICINE, 2013, 65 :750-764