2. Academic Validation
  3. MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation

MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation

  • Cell Death Dis. 2020 Apr 20;11(4):256. doi: 10.1038/s41419-020-2424-1.
Jun Zheng  # 1 2,  Liang Chen  # 1 2,  Tongyu Lu  # 1 2,  Yingcai Zhang  # 1 2,  Xin Sui 3,  Yang Li 1 2,  Xuna Huang 4,  Liying He 5,  Jianye Cai 1 2,  Chaorong Zhou 1 2,  Jinliang Liang 2,  Guihua Chen 6 7,  Jia Yao 8 9,  Yang Yang 10 11
Affiliations

Affiliations

  • 1 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China.
  • 2 Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China.
  • 3 Surgical Intensive Care Unit, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China.
  • 4 Central Experimental Room of the Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China.
  • 5 Department of Gastroenterology, Guangzhou Women and Children's Medical Center, 510630, Guangzhou, China.
  • 6 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China. chgh1955@263.net.
  • 7 Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China. chgh1955@263.net.
  • 8 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China. yaojia6@mail.sysu.edu.cn.
  • 9 Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China. yaojia6@mail.sysu.edu.cn.
  • 10 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China. yysysu@163.com.
  • 11 Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, 510630, Guangzhou, China. yysysu@163.com.
  • # Contributed equally.
PMID: 32312955 DOI: 10.1038/s41419-020-2424-1
Abstract

Hepatocyte Apoptosis is the main pathophysiological process underlying liver ischemia/reperfusion (I/R) injury. Mitochondrial abnormalities have a vital role in hepatocellular damage. The hepatoprotective effects of mesenchymal stem cells (MSCs) have been previously demonstrated. In this study, we aim to investigate the effect and potential mechanism of MSCs against liver I/R injury. Effects of MSCs were studied in mice liver I/R injury model and in a hypoxia/reoxygenation (H/R) model of L02 hepatocytes. The potential mechanisms of MSCs on these in vivo and in vitro I/R-induced hepatocellular Apoptosis models were studies. Accompanied by the improvement of hepatic damage, MSCs exhibited capabilities of controlling mitochondrial quality, shown by reduced mitochondrial Reactive Oxygen Species (mtROS) overproduction, decreased the accumulation of mitochondrial fragmentation, restored ATP generation and upregulated Mitophagy. Furthermore, we descripted a potential mechanism of MSCs on upregulating Mitophagy and found that the reduced Parkin and PINK1 expression and inactivated AMPKα pathway were observed in the liver tissue in I/R model. These effects were reversed by MSCs treatment. In vitro study showed that MSC-conditioned medium (MSC-CM) suppressed hepatocellular Apoptosis and inhibited mtROS accumulation in the H/R environment. And these effects of MSC-CM were partially blocked after the cells were transfected with PINK1 siRNA or added with dorsomorphin. Collectively, our findings provide a novel pharmacological mechanism that MSCs exert hepatoprotective effect in liver I/R injury via upregulating PINK1-dependent Mitophagy. In addition, this effect might be attributed to the modulation of AMPKα activation.

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