The Reactive Oxygen Species–Mitophagy Signaling Pathway Regulates Liver Endothelial Cell Survival During Ischemia/Reperfusion Injury

Bhogal, Ricky H.; Weston, Chris J.; Velduis, Susanne; Leuvenink, Henri G. D.; Reynolds, Gary; Davies, Sarah; Nyguet-Thin, Luu; Alfaifi, Mohammed; Shepard, Emma L.; Boteon, Yuri L.; Wallace, Lorraine; Oo, Ye Htun; Adams, David H.; Mirza, Darius F.; Mergental, Hynek; Muirhead, Gillian; Stephenson, B.; Afford, Simon C.

doi:10.1002/lt.25313

Cited by 31 publications

(20 citation statements)

References 48 publications

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“…FUNDC1-related mitophagy suppresses hepatocarcinogenesis via inhibition of inflammasome activation [6], [7]. During liver ischemia-reperfusion injury, ROS-modified mitophagy regulates liver endothelial cell apoptosis [8]. In NAFLD, mitophagy is significantly inhibited and defective mitophagy is deemed as the pathogenesis for the development of fatty liver disease [9].…”

Section: Introductionmentioning

confidence: 99%

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

et al. 2019

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Obesity-related non-alcoholic fatty liver disease (NAFLD) is connected with mitochondrial stress and hepatocyte apoptosis. Parkin-related mitophagy sustains mitochondrial homeostasis and hepatocyte viability. However, the contribution and regulatory mechanisms of Parkin-related mitophagy in NAFLD are incompletely understood. Macrophage stimulating 1 (Mst1) is a novel mitophagy upstream regulator which excerbates heart and cancer apoptosisn via repressing mitophagy activity. The aim of our study is to explore whether Mst1 contributes to NAFLD via disrupting Parkin-related mitophagy. A NAFLD model was generated in wild-type (WT) mice and Mst1 knockout (Mst1-KO) mice using high-fat diet (HFD). Cell experiments were conducted via palmitic acid (PA) treatment in the primary hepatocytes. The results in our study demonstrated that Mst1 was significantly upregulated in HFD-treated livers. Genetic ablation of Mst1 attenuated HFD-mediated hepatic injury and sustained hepatocyte viability. Functional studies illustrated that Mst1 knockdown reversed Parkin-related mitophagy and the latter protected mitochondria and hepatocytes against HFD challenge. Besides, we further figured out that Mst1 modulated Parkin expression via the AMPK pathway; blockade of AMPK repressed Parkin-related mitophagy and recalled hepatocytes mitochondrial apoptosis. Altogether, our data identified that NAFLD was closely associated with the defective Parkin-related mitophagy due to Mst1 upregulation. This finding may pave the road to new therapeutic modalities for the treatment of fatty liver disease.

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Section: Introductionmentioning

confidence: 99%

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

et al. 2019

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“…When reperfusion initiates, the reestablishment of the electron transfer chain and ATP synthesis in mitochondria enables autophagy to eliminate abnormal proteins and organelles that are produced during ischemia. Enhanced hepatic mitophagy is observed at the early stages of IR in both in vivo and in vitro models, which is associated with elevated cell death and aggregated liver injury [164][165][166]. However, the autophagy capacity also becomes impaired following prolonged ischemia, which may not be sufficient to eliminate the accumulated dysfunctional mitochondria.…”

Section: Mitophagy In Liver Ischemia/reperfusion Injurymentioning

confidence: 99%

Role and Mechanisms of Mitophagy in Liver Diseases

McKeen

Zhang

et al. 2020

Cells

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The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver’s physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.

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“…However, parkin deficiency elevates HIRI by decreasing mitochondrial autophagy and increasing apoptosis. Bhogal et al (2018) found that autophagy within LEC is reduced accompanying IRI increased cell death. demonstrated that impairing mitophagy contributed to aggravation of hepatic ischemia-reperfusion injury in aging mice.…”

Section: Discussionmentioning

confidence: 97%

Peer Review #1 of "Inhibition of excessive mitophagy by N-acetyl-L-tryptophan confers hepatoprotection against Ischemia-Reperfusion injury in rats (v0.1)"

2020

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In order to investigate the mechnism of hepatoprotective of N-acetyl-L-tryptophan (L-NAT) against ischemia-reperfusion (I/R) injury, the effects of L-NAT were investigated in hepatic ischemia-reperfusion injury (HIRI) models both in vitro and in vivo, which were made by BRL cells and Sprague-Dawley (SD) rats, respectively. The cell viability of hepatocyte was assessed by cell counting kit-8 (CCK-8) staining. The activation of autophagy was detected by electron microscopy (EM), quantitative real-time PCR (qRT-PCR), Western Blotting and immunofluorescence. The activation of mitophagy was determined by the change of autophagy related protein, change of mitochondrial structure and function, co-location of autophagy protein and MitoTracker. Results showed that the morphological structures of hepatocytes were changed significantly after HIRI, and the cell viability of hydrogen peroxide (H 2 O 2)-induced BRL cells was decreased. Autophagy markers Beclin1, microtubule associated protein 1 light chain 3-Ⅱ (LC3-Ⅱ) and autophagy related protein-7 (ATG-7) were highly expressed and the expression of SQSTM1 (P62) was decreased after HIRI, which suggested that autophagy of hepatocytes was activated after I/R. The reduction of ATP, mitochondrial DNA (mtDNA) and the mitochondrial transmembrane potential (ΔΨm) after H 2 O 2-induced revealed that function of mitochondrial had also undergone significant changes. The increased expression of autophagy protein, destructure of mitochondria and mitochondrial dysfunction, the increased co-location of Beclin1 and MitoTracker induced by H 2 O 2 implied the excessive mitophagy. The expression of autophagy protein was increased by 3-Methyladenine (3-MA), providing another piece of evidence. Importantly, all changes were restored by L-NAT pretreament. In conclusion, the present findings demonstrate that excessive mitophagy involved in the process of HIRI and L-NAT may protect hepatocytes against HIRI by inhibiting activation of mitophagy and improving the structure and function

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The Reactive Oxygen Species–Mitophagy Signaling Pathway Regulates Liver Endothelial Cell Survival During Ischemia/Reperfusion Injury

Cited by 31 publications

References 48 publications

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

Role and Mechanisms of Mitophagy in Liver Diseases

Peer Review #1 of "Inhibition of excessive mitophagy by N-acetyl-L-tryptophan confers hepatoprotection against Ischemia-Reperfusion injury in rats (v0.1)"

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