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

Chen Y, Lv L, Jiang Z, Yang H, Li S, Jiang Y - PLoS ONE (2013)

Bottom Line: In line with the mitochondrial dysfunction, the expression of Mfn2 decreased significantly under GCDCA treatment conditions.Increasing the expression of truncated Mfn2 also had a protective effect against the hepatotoxicity of GCDCA.Therapeutic approaches that target Mfn2 may have protective effects against hepatotoxic of bile acids during cholestasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital, Fuzhou, China. cybiao717@sina.com.cn

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.

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Effect of the overexpression of Mfn2 or the truncated Mfn2 mutant on mitochondrial function in GCDCA-treated L02 cells.The overexpression of Mfn2 or truncated Mfn2 (A) protected cell viability in L02 cells, (B) reversed the reduction in ATP levels, (C) ameliorated the decrease in ΔΨm, and (D) reduced the excess ROS production following treatment with GCDCA. The results are expressed as a percentage of the control value, which was set at 100%. The values are the means ± SEM. *P<0.05 versus the control group, #P<0.05, ##P<0.01 versus the GCDCA group, n = 6.
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pone-0065455-g005: Effect of the overexpression of Mfn2 or the truncated Mfn2 mutant on mitochondrial function in GCDCA-treated L02 cells.The overexpression of Mfn2 or truncated Mfn2 (A) protected cell viability in L02 cells, (B) reversed the reduction in ATP levels, (C) ameliorated the decrease in ΔΨm, and (D) reduced the excess ROS production following treatment with GCDCA. The results are expressed as a percentage of the control value, which was set at 100%. The values are the means ± SEM. *P<0.05 versus the control group, #P<0.05, ##P<0.01 versus the GCDCA group, n = 6.

Mentions: Previous studies have demonstrated that Mfn2 overexpression affects the morphology of mitochondrial filaments and restores mitochondrial function. To determine whether the effects of Mfn2 on mitochondrial metabolism could be a consequence of mitochondrial fusion, we generated a truncated Mfn2 mutant (hMfn2D602–757) that lacked the amino acid residues from 602 to 757 and therefore lacked the transmembrane domain and the normal C-terminal end. In the present study, confocal microscopy revealed that most of the truncated Mfn2 was observed in the mitochondria, similar to the localization of wild-type Mfn2. However, the overexpression of truncated Mfn2 in the L02 cells did not block the mitochondrial fragmentation induced by GCDCA (Fig. 4B and 4C). Compared with wild-type Mfn2, truncated Mfn2 remained effective in reversing mitochondrial dysfunction in GCDCA-treated L02 cells (Fig. 5A, B, C, D).


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

Chen Y, Lv L, Jiang Z, Yang H, Li S, Jiang Y - PLoS ONE (2013)

Effect of the overexpression of Mfn2 or the truncated Mfn2 mutant on mitochondrial function in GCDCA-treated L02 cells.The overexpression of Mfn2 or truncated Mfn2 (A) protected cell viability in L02 cells, (B) reversed the reduction in ATP levels, (C) ameliorated the decrease in ΔΨm, and (D) reduced the excess ROS production following treatment with GCDCA. The results are expressed as a percentage of the control value, which was set at 100%. The values are the means ± SEM. *P<0.05 versus the control group, #P<0.05, ##P<0.01 versus the GCDCA group, n = 6.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675030&req=5

pone-0065455-g005: Effect of the overexpression of Mfn2 or the truncated Mfn2 mutant on mitochondrial function in GCDCA-treated L02 cells.The overexpression of Mfn2 or truncated Mfn2 (A) protected cell viability in L02 cells, (B) reversed the reduction in ATP levels, (C) ameliorated the decrease in ΔΨm, and (D) reduced the excess ROS production following treatment with GCDCA. The results are expressed as a percentage of the control value, which was set at 100%. The values are the means ± SEM. *P<0.05 versus the control group, #P<0.05, ##P<0.01 versus the GCDCA group, n = 6.
Mentions: Previous studies have demonstrated that Mfn2 overexpression affects the morphology of mitochondrial filaments and restores mitochondrial function. To determine whether the effects of Mfn2 on mitochondrial metabolism could be a consequence of mitochondrial fusion, we generated a truncated Mfn2 mutant (hMfn2D602–757) that lacked the amino acid residues from 602 to 757 and therefore lacked the transmembrane domain and the normal C-terminal end. In the present study, confocal microscopy revealed that most of the truncated Mfn2 was observed in the mitochondria, similar to the localization of wild-type Mfn2. However, the overexpression of truncated Mfn2 in the L02 cells did not block the mitochondrial fragmentation induced by GCDCA (Fig. 4B and 4C). Compared with wild-type Mfn2, truncated Mfn2 remained effective in reversing mitochondrial dysfunction in GCDCA-treated L02 cells (Fig. 5A, B, C, D).

Bottom Line: In line with the mitochondrial dysfunction, the expression of Mfn2 decreased significantly under GCDCA treatment conditions.Increasing the expression of truncated Mfn2 also had a protective effect against the hepatotoxicity of GCDCA.Therapeutic approaches that target Mfn2 may have protective effects against hepatotoxic of bile acids during cholestasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital, Fuzhou, China. cybiao717@sina.com.cn

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.

Show MeSH
Related in: MedlinePlus