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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00601

Mitofusin2, as a protective target in the liver, controls the balance of apoptosis and autophagy in acute-on-chronic liver failure

Ran Xue1, Jing Yang1, Lin Jia1, Xuemin Zhu1, Jing Wu1, Yueke Zhu1 and  Qinghua Meng1*
  • 1Beijing Youan Hospital, Capital Medical University, China

Aim
Acute-on-chronic liver failure (ACLF) is closely related to mitochondrial dysfunction. Previous studies showed the vital role of mitofusin2 (Mfn2) in the regulation of mitochondrial function. However, the effect of Mfn2 on ACLF remains unknown. As one of mitochondrial-related pathways, BNIP3-mediated pathway controls the balance between apoptosis and autophagy. However, the relationship between Mfn2 and BNIP3-mediated pathway in ACLF is still obscure. The aim of our study is to clarify the effect of Mfn2 and potential molecular mechanisms in ACLF.
Methods
We collected liver tissue from ACLF patients and constructed an ACLF animal model and a hepatocyte autophagy injury model, using adenovirus and lentivirus to deliver Mfn2 and Mfn2-siRNA to liver cells, in order to assess the effect of Mfn2 on autophagy and apoptosis in ACLF. We explored the biological mechanisms of Mfn2-induced autophagy and apoptosis of ACLF through western blotting, RT-PCR, transmission electron microscopy, immunofluorescence, immunohistochemical staining and Hematoxylin-Eosin staining.
Results
Compared with the normal liver tissue, the expressions of Mfn2, Atg5, Beclin1 and LC3-II/I were significantly decreased and the expression of P62 was much higher in patients with ACLF. Mfn2 significantly attenuated ACLF, characterized via microscopic histopathology and reduced serum AST and ALT levels. Mfn2 promoted the expressions of ATP Synthase β, Atg5, Beclin1, LC3-II/I and Bcl2 and reduced the expressions of P62, Bax and BNIP3.
Conclusions
Mfn2 plays a protective role in the progression of ACLF. BNIP3-mediated signaling pathway is not the only factor associated with Mfn2 controlling the balance of apoptosis and autophagy in ACLF. Mfn2 will provide a promising therapeutic target for patients with ACLF.

Keywords: Mitofusin2, Acute-on-chronic liver failure, Autophagy, Apoptosis, liver damage

Received: 24 Feb 2019; Accepted: 10 May 2019.

Edited by:

David Sacerdoti, University of Padova, Italy

Reviewed by:

Hasibur Rehman, University of Alabama at Birmingham, United States
Dr. SHAILENDRA P. SINGH, New York Medical College, United States  

Copyright: © 2019 Xue, Yang, Jia, Zhu, Wu, Zhu and Meng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Qinghua Meng, Beijing Youan Hospital, Capital Medical University, Beijing, Beijing Municipality, China, meng_qh@126.com