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  3. Oxidative stress-dependent frataxin inhibition mediated alcoholic hepatocytotoxicity through ferroptosis

Oxidative stress-dependent frataxin inhibition mediated alcoholic hepatocytotoxicity through ferroptosis

  • Toxicology. 2020 Dec 1;445:152584. doi: 10.1016/j.tox.2020.152584.
Jingjing Liu 1,  Hui He 2,  Jing Wang 3,  Xiaoping Guo 1,  Hongkun Lin 1,  Huimin Chen 1,  Chunjie Jiang 1,  Li Chen 1,  Ping Yao 4,  Yuhan Tang 5
Affiliations

Affiliations

  • 1 Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Department of Preventive Medicine, Changzhi Medical College, Changzhi 046000, China.
  • 3 Preventive Medicine Experimental Teaching Center, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 4 Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: yaoping@mails.tjmu.edu.cn.
  • 5 Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: tyh043@126.com.
PMID: 33017621 DOI: 10.1016/j.tox.2020.152584
Abstract

Alcoholic liver disease (ALD) is one of the severe liver diseases, resulting in high morbidity and mortality. However, frataxin, a mitochondrial protein mainly participating in iron homeostasis and oxidative stress, remains uncertain in the pathogenesis of ALD. In the present study, the role of frataxin in ALD was investigated. Ethanol (100 mM) decreased frataxin expression at 48 and 72 h in HepG2. Dramatically, in HepG2 overexpressing Cytochrome P450 2E1 (HepG2CYP2E1+/+), frataxin level was down-regulated with ethanol stimulation at 12 h. Moreover, chronically feeding ethanol to mice via Lieber-DeCarli liquid diet (30 % of total calories) for 15 weeks significantly inhibited frataxin expression. Ferroptosis signature proteins were dysregulated, accompanied by mitochondrial damage of morphology, enhanced malondialdehyde and decreased glutathione in the liver, as well as accumulation of Reactive Oxygen Species and mitochondrial labile iron pool in primary hepatocytes. Notably, proteomics screening of frataxin deficient-HepG2 further suggested frataxin was associated with Ferroptosis. Furthermore, the Ferroptosis inhibitor ferrostatin-1 blocked the increase of Lactate Dehydrogenase release by ethanol in HepG2CYP2E1+/+. Most importantly, frataxin deficiency enhanced Ferroptosis driven by ethanol via evaluating the levels of Lactate Dehydrogenase, cell morphological changes, mitochondrial labile iron pool, and lipid peroxidation. Conversely, restoring frataxin alleviated the sensitivity to Ferroptosis. In addition, frataxin overexpression mitigated the sensitivity of ethanol-induced Ferroptosis in HepG2CYP2E1+/+. Collectively, our study revealed that frataxin-mediated Ferroptosis contributed to ALD, highlighting a potential therapeutic strategy for ALD.

Keywords

Alcoholic liver disease; Ferroptosis; Frataxin; Oxidative stress.

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