Mitofusin 2 protects hepatocyte mitochondrial function from damage induced by GCDCA.

Abstract

Mitochondrial impairment is hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Mitofusin 2 (Mfn2) regulates mitochondrial morphology and signaling and is involved in the development of numerous mitochondrial-related diseases; however, a functional role for Mfn2 in chronic liver cholestasis which is characterized by increased levels of toxic bile acids remain unknown. Therefore, the aims of this study were to evaluate the expression levels of Mfn2 in liver samples from patients with extrahepatic cholestasis and to investigate the role Mfn2 during bile acid induced injury in vitro. Endogenous Mfn2 expression decreased in patients with extrahepatic cholestasis. Glycochenodeoxycholic acid (GCDCA) is the main toxic component of bile acid in patients with extrahepatic cholestasis. In human normal hepatocyte cells (L02), Mfn2 plays an important role in GCDCA-induced mitochondrial damage and changes in mitochondrial morphology. In line with the mitochondrial dysfunction, the expression of Mfn2 decreased significantly under GCDCA treatment conditions. Moreover, the overexpression of Mfn2 effectively attenuated mitochondrial fragmentation and reversed the mitochondrial damage observed in GCDCA-treated L02 cells. Notably, a truncated Mfn2 mutant that lacked the normal C-terminal domain lost the capacity to induce mitochondrial fusion. Increasing the expression of truncated Mfn2 also had a protective effect against the hepatotoxicity of GCDCA. Taken together, these findings indicate that the loss of Mfn2 may play a crucial role the pathogenesis of the liver damage that is observed in patients with extrahepatic cholestasis. The findings also indicate that Mfn2 may directly regulate mitochondrial metabolism independently of its primary fusion function. Therapeutic approaches that target Mfn2 may have protective effects against hepatotoxic of bile acids during cholestasis.

• Authors: Yongbiao Chen, Lizhi Lv, Zhelong Jiang, Hejun Yang, Song Li, Yi Jiang
• Journal: PloS one (PLoS One) Vol. 8 Issue 6 Pg. e65455 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23755235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Mitochondrial Proteins
• Glycochenodeoxycholic Acid
• Adenosine Triphosphate
• GTP Phosphohydrolases
• MFN2 protein, human

Topics

• Adenosine Triphosphate (metabolism)
• Adult
• Cell Line
• Cell Survival (drug effects)
• Female
• GTP Phosphohydrolases (genetics, metabolism)
• Glycochenodeoxycholic Acid (pharmacology)
• Hepatocytes (drug effects, metabolism)
• Humans
• Liver (drug effects, metabolism)
• Male
• Middle Aged
• Mitochondria (drug effects, metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• Oxidative Stress (drug effects)