Activation of UQCRC2-dependent mitophagy by tetramethylpyrazine inhibits MLKL-mediated hepatocyte necroptosis in alcoholic liver disease

Zhou, Ying; Wu, Ruoman; Wang, Xinqi; Jiang, Yiming; Xu, Wenxuan; Shao, Yunyun; Yue, Chunxiao; Shi, Wenqian; Jin, Huanhuan; Ge, Ting; Bao, Xiaofeng; Lu, Chunfeng

doi:10.1016/j.freeradbiomed.2021.11.008

Cited by 26 publications

(11 citation statements)

References 46 publications

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“…Finally, we explored whether MSC-ex regulates LX-2 cell death through holding necroptosis. MLKL is considered a central executor of necroptosis, and phosphorylation of MLKL (p-MLKL) was a critical event of necroptosis [ 31 ]. MSC-ex treatment significantly increased p-MLKL expression in LX-2 cells, which was reverted by Necroptosis inhibitor NEC-1 or NEC-1s (Supplemental Figs.…”

Section: Resultsmentioning

confidence: 99%

HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis

et al. 2022

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Activated hepatic stellate cells (HSCs) are significant in liver fibrosis. Our past investigations have shown that human umbilical cord mesenchymal stem cells (hucMSCs) and their secreted exosomes (MSC-ex) could alleviate liver fibrosis via restraining HSCs activation. However, the mechanisms underlying the efficacy were not clear. Ferroptosis is a regulatory cell death caused by excessive lipid peroxidation, and it plays a vital role in the occurrence and development of liver fibrosis. In the present study, we aimed to study the proferroptosis effect and mechanism of MSC-ex in HSCs. MSC-ex were collected and purified from human umbilical cord MSCs. Proferroptosis effect of MSC-ex was examined in HSCs line LX-2 and CCl4 induced liver fibrosis in mice. Gene knockdown or overexpression approaches were used to investigate the biofactors in MSC-ex-mediated ferroptosis regulation. Results: MSC-ex could trigger HSCs ferroptosis by promoting ferroptosis-like cell death, ROS formation, mitochondrial dysfunction, Fe2+ release, and lipid peroxidation in human HSCs line LX-2. Glutathione peroxidase 4 (GPX4) is a crucial regulator of ferroptosis. We found that intravenous injection of MSC-ex significantly decreased glutathione peroxidase 4 (GPX4) expression in activated HSCs and collagen deposition in experimental mouse fibrotic livers. Mechanistically, MSC-ex derived BECN1 promoted HSCs ferroptosis by suppressing xCT-driven GPX4 expression. In addition, ferritinophagy and necroptosis might also play a role in MSC-ex-promoted LX-2 cell death. Knockdown of BECN1 in MSC diminished proferroptosis and anti-fibrosis effects of MSC-ex in LX-2 and fibrotic livers. MSC-ex may promote xCT/GPX4 mediated HSCs ferroptosis through the delivery of BECN1 and highlights BECN1 as a potential biofactor for alleviating liver fibrosis.

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Section: Resultsmentioning

confidence: 99%

HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis

et al. 2022

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“…Reports show that within 6 h of a single ethanol intraperitoneal injection to rats, the mitochondrial protein ubiquitin ligase parkin was translocated to mitophagosomes and mitophagy was enhanced in rat liver . However, a newly published paper has revealed an opposite phenomenon in separated mice primary hepatocytes, as a 24 h alcohol exposure blocked mitophagy . Our findings show that chronic and binge ethanol treatments reduced mice liver mitophagy through an AMPK–Ulk1-dependent pathway.…”

Section: Discussionmentioning

confidence: 47%

“…30 However, a newly published paper has revealed an opposite phenomenon in separated mice primary hepatocytes, as a 24 h alcohol exposure blocked mitophagy. 31 Our findings show that chronic and binge ethanol treatments reduced mice liver mitophagy through an AMPK−Ulk1-dependent pathway.…”

Section: ■ Discussionmentioning

confidence: 60%

Tangeretin Protects Mice from Alcohol-Induced Fatty Liver by Activating Mitophagy through the AMPK–ULK1 Pathway

Guo

Chen

Fang

et al. 2022

J. Agric. Food Chem.

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Alcoholic beverages are widely consumed all over the world, but continuous ethanol exposure leads to hepatic steatosis that, without proper treatment, will later develop into severe liver disorders. In this study, we investigated the potential protective effect of tangeretin, a flavonoid derived from citrus peel, against alcoholic fatty liver. The in vivo effects of tangeretin were analyzed by oral intake in a chronic-binge alcohol feeding C57BL/6j mouse model, while the underlying mechanism was explored by in vitro studies performed on ethanol-treated hepatic AML-12 cells. Ethanol feeding increased the serum alanine aminotransferase and aspartate aminotransferase levels, the liver weight, and the serum and liver triacylglycerol contents, whereas 20 and 40 mg/kg tangeretin treatment promoted a dose-dependent suppression of these effects. Interestingly, tangeretin prevented increases in the liver oxidative stress level and protected the hepatocyte mitochondria from ethanol-induced morphologic abnormalities. A mechanistic study showed that 20 μM tangeretin treatment activated mitophagy through an AMP-activated protein kinase (AMPK)–uncoordinated 51-like kinase 1 (Ulk1) pathway, thereby restoring mitochondria respiratory function and suppressing steatosis. By contrast, blocking the AMPK–Ulk1 pathway with compound C reversed the hepatoprotective effect of tangeretin. Overall, tangeretin activated mitophagy and protected against ethanol-induced hepatic steatosis through an AMPK–Ulk1-dependent mechanism.

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“…Although autophagy can alleviate hepatocyte apoptosis and steatosis in acute alcohol liver disease ( 35 ), decrease autophagic flux in hepatocyte is observed in models of chronic alcohol exposure ( 36 , 37 ). A significant decrease in UQCRC2 protein expression cause impaired mitophagy, which may aggravate MLKL-mediated hepatocyte necroptosis and inflammation in alcoholic liver disease ( 38 , 39 ). Furthermore, early autophagy enhance HBV infection and envelopment ( 40 ).…”

Section: Autophagy Dysregulation In Hepatocytes Leads To Liver Inflam...mentioning

confidence: 99%

Hepatocytes: A key role in liver inflammation

Gong

Liu

et al. 2023

Front. Immunol.

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Hepatocytes, the major parenchymal cells in the liver, are responsible for a variety of cellular functions including carbohydrate, lipid and protein metabolism, detoxification and immune cell activation to maintain liver homeotasis. Recent studies show hepatocytes play a pivotal role in liver inflammation. After receiving liver insults and inflammatory signals, hepatocytes may undergo organelle damage, and further respond by releasing mediators and expressing molecules that can act in the microenvironment as well as initiate a robust inflammatory response. In this review, we summarize how the hepatic organelle damage link to liver inflammation and introduce numerous hepatocyte-derived pro-inflammatory factors in response to chronic liver injury.

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Activation of UQCRC2-dependent mitophagy by tetramethylpyrazine inhibits MLKL-mediated hepatocyte necroptosis in alcoholic liver disease

Cited by 26 publications

References 46 publications

HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis

HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis

Tangeretin Protects Mice from Alcohol-Induced Fatty Liver by Activating Mitophagy through the AMPK–ULK1 Pathway

Hepatocytes: A key role in liver inflammation

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