Mitofusin2, as a Protective Target in the Liver, Controls the Balance of Apoptosis and Autophagy in Acute-on-Chronic Liver Failure.

Ran Xue,Xuemin Zhu,Jing Wu,Yueke Zhu,Jing Yang,Qinghua Meng,Lin Jia

doi:10.3389/fphar.2019.00601

Abstract

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, Quantitative Real-Time PCR (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.

Highlights

Acute-on-chronic liver failure (ACLF) is an acute decompensation of chronic liver disease complicated with other organ failure (Olson, 2019)
As for the level of autophagy, the expressions of Atg5, Beclin1, and LC3-II/I were significantly lower and the expression of P62 was much higher in ACLF patients (Figure 1B)
In our study, mitochondrial fusion protein 2 (Mfn2) promoted the level of autophagy in ACLF, which is opposite to the expression of BNIP3. It indicated that the BNIP3-mediated signaling pathway is not the only factor associated with Mfn2 controlling the balance of apoptosis and autophagy in ACLF

Summary

Introduction

Acute-on-chronic liver failure (ACLF) is an acute decompensation of chronic liver disease complicated with other organ failure (Olson, 2019). Despite progression of clinical treatments, ACLF is still associated with increased mortality and morbidity (Xue et al, 2017a; Xue et al, 2017b). It is one of the mainly causes for clinical problems that pathogenesis and progression of ACLF are not fully understood. The mitochondrion is one of the most important organelles for energy metabolism, and its dysfunction is closely related to the incidence of liver failure (Mansouri et al, 2018; Waltz et al, 2018) It performs its biological functions through continuous division and fusion (Xue et al, 2018), and many proteins take part in these processes, such as mitofusin 1 (Mfn1), optic atrophy 1 (OPA1), dynamin-related protein (DRP1), and mitochondrial fission 1 protein (Fis1) (Singh et al, 2016a; Singh et al, 2016b; Sacerdoti et al, 2018)

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