Specific Overexpression of Mitofusin-2 in Hepatic Stellate Cells Ameliorates Liver Fibrosis in Mice Model

Abstract

{These authors contributed equally to this study.Liver fibrosis is a chronic liver disease that could further develop to cirrhosis and liver carcinoma. Hepatic stellate cells (HSCs) are primary effector cells to initiate liver fibrosis. We aimed to explore the function and underlying mechanisms of mitochondrial fusion protein Mitofusin-2 (MFN2) in liver fibrosis. First, we utilized an alpha-smooth muscle actin promoter to overexpress MFN2 specifically in HSCs using adeno-associated virus (AAV) vector (AAV-MFN2). Overexpression of MFN2 was specifically achieved in HSC-T6 cells, but not in murine bone marrow-derived macrophages or hepatocyte AML-12 cells. We found that high expression of MFN2 induced apoptosis of HSC-T6 cells. Mechanistically, we demonstrated that high level of MFN2 inhibited TGF-b1/Smad signaling pathway, triggered downregulation of type I, type III, and type IV collagen, and antagonized the formation of factors associated with liver fibrosis. Furthermore, we found that overexpression of MFN2 using AAV-MFN2 ameliorated CCl 4 -induced liver fibrosis in vivo with significantly decreased immune cell infiltration. Taken together, our findings indicate that MFN2 is critical in regulating apoptosis and liver fibrosis in HSCs, which might be a useful therapeutic target to treat liver fibrosis.

Role of Mitofusins and Mitophagy in Life or Death Decisions

“…The most described links are with prevalent neuropathies such as Parkinson’s and Alzheimer’s disease ( Han et al, 2011 ; Lee et al, 2012 ; Stuppia et al, 2015 ; Gao et al, 2017 ), cardiac dysfunction ( Hall et al, 2014 ; Nan et al, 2017 ; Dorn, 2018 ; Hernandez-Resendiz et al, 2020 ), type 2 diabetes, obesity and insulin resistance ( Zorzano et al, 2009 ; Dai and Jiang, 2019 ) and cancer ( Allegra et al, 2019 ). Finally, MFN2 has also been associated with progression of liver diseases such as acute-on-chronic liver failure (ACLF) and NAFLD ( Wang et al, 2013 ; Hernández-Alvarez et al, 2019 ; Xue et al, 2019a , b ) and proposed as a possible therapeutic target for hepatic inflammation and fibrosis ( Zhu et al, 2020 ).…”

Scoparone alleviates hepatic fibrosis by inhibiting the TLR‐4/NF‐κB pathway

“…Furthermore, HA, LN, PC‐III, and IV‐C can be regarded as auxiliary evaluation indicators to determine the prognosis and therapeutic efficacy of hepatic fibrosis (Qu et al, 2014; Zhang et al, 2016). Importantly, given that TGF‐β1 and α‐SMA are both significant proteins that play a role in the development so liver fibrosis (H. Zhu et al, 2020). In our in vivo experiments, we found that the liver tissue structure was severely damaged after treatment with CCl 4 (Figure 1d), where collagen was excessively accumulated (Figure 2b), and ALT, AST, ALP, γ‐GT, and TBIL had a significant rise in the activity or there was an elevated content of HA, LN, PC‐III, IV‐C, α‐SMA, and TGF‐β1 (Figures 1–2).…”

Mitochondrial Dynamics and Liver Cancer

“…Moreover, hepatic depletion of MFN2 in mice causes a NASH-like condition characterized by hepatic steatosis, inflammation, and fibrosis [ 36 ]. Regarding liver fibrosis, which is a risk factor in the development of cirrhosis and HCC [ 75 ], high expression of MFN2 protein inhibits the Transforming growth factor beta 1/Smad (TGF-β1/Smad) signaling pathway, thus triggering the downregulation of type I, type III, and type IV collagen and reducing the formation of factors associated with liver fibrosis [ 76 ]. Furthermore, MFN2 overexpression using AAV-MFN2 was found to improve carbon-tetrachloride-induced liver fibrosis in vivo [ 76 ].…”

“…Regarding liver fibrosis, which is a risk factor in the development of cirrhosis and HCC [ 75 ], high expression of MFN2 protein inhibits the Transforming growth factor beta 1/Smad (TGF-β1/Smad) signaling pathway, thus triggering the downregulation of type I, type III, and type IV collagen and reducing the formation of factors associated with liver fibrosis [ 76 ]. Furthermore, MFN2 overexpression using AAV-MFN2 was found to improve carbon-tetrachloride-induced liver fibrosis in vivo [ 76 ]. In keeping with these observations, specific deletion of MFN2 in liver causes ER stress, which leads to a chronic inflammatory state that in turn causes the activation of TGF-β1 and deposition of collagen, with the subsequent development of liver cancer [ 36 ].…”