Mitofusin2, a rising star in acute‐on‐chronic liver failure, triggers macroautophagy via the mTOR signalling pathway

Abstract

Acute‐on‐chronic liver failure (ACLF) is a life‐threatening syndrome with poor prognosis. Several studies have begun to prove that mitochondria play a crucial role in liver failure. Mitofusin2 (Mfn2) plays a key role in maintaining the integrity of mitochondrial morphology and function. However, the role and underlying mechanisms of Mfn2 on cell autophagy of ACLF remain unclear. Our aim was to explore the effect of Mfn2 on several biological functions involving cell autophagy in ACLF. In this study, we constructed an ACLF animal model and a hepatocyte autophagy model, using adenovirus and lentivirus to deliver Mfn2 to liver cells, in order to assess the effect of Mfn2 on autophagy and apoptosis in ACLF. Furthermore, we explored the biological mechanism of Mfn2‐induced autophagy of ACLF using Western blotting, RT‐PCR and electron microscopy. We found that Mfn2 significantly attenuated ACLF, characterized by ameliorated gross appearance and microscopic histopathology of liver, and reduced serum AST, ALT, and TBIL levels. Mfn2 improved the expressions of LC3‐II, Atg5 and Bcl‐2 and down‐regulated the expression of P62 and Bax in ACLF. Like rapamycin, Mfn2 also significantly inhibited the expressions of p‐PI3K, p‐Akt and p‐mTOR in ACLF. In conclusion, our findings suggest that Mfn2 influences multiple biological functions of ACLF via the PI3K/Akt/mTOR signalling pathway. This study will provide a reliable theoretical basis for the application of Mfn2 as an effective target for ACLF treatment, reversing or delaying the process of ACLF.

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 ).…”

“…Mitofusin 2 downregulation, causing decreased mitophagy or autophagy, was also observed in cardiac injury mimicked by angiotensin II ( Xiong et al, 2019 ), in intervertebral disc degeneration (IVDD) ( Chen et al, 2020 ) and in acute-on-chronic liver failure (ACLF) ( Xue et al, 2019a , b ). Common to these reports, low levels of MFN2/Mfn2 and concomitant decrease in autophagy/mitophagy were accompanied by apoptosis induction.…”

HMGB1-Induced Hepatocyte Pyroptosis Expanding Inflammatory Responses Contributes to the Pathogenesis of Acute-on-Chronic Liver Failure (ACLF)

“…The treatment groups included the ACLF model group (n=12), the HMGB1 inhibitor group (n=10), the Caspase-1 inhibitor group (n=10), and the HMGB1 inhibitor+Caspase-1 inhibitor group (n=10). The ACLF rat model was established in the treatment groups according to a previously reported method, 1 , 17 and with the following operations performed:…”

“…Acute-on-chronic liver failure (ACLF) is a severe life-threatening disease that develops extremely rapidly, with a short-term mortality rate as high as 50%-90%. 1 There is no consensus definition of ACLF yet between Eastern and Western medicine. The “Guideline for Diagnosis and Treatment of Liver Failure (2018 Edition)” states that ACLF refers to liver failure manifestations, such as acute jaundice and coagulation dysfunction, caused by various inducements on the basis of chronic liver disease, which can combine with multiple complications such as hepatic encephalopathy, ascites, infection, etc.…”

Detoxification II Prescription Suppresses the Th-17/IL-17 Inflammatory Axis to Improve the Liver Function of ACLF-Rats via Inactivating the P38MAPK Pathway

“…e study has showed that the acute-on-chronic liver failure (ACLF) is one of the serious liver-related diseases with high mortality [3]. Statistically, the short-term mortality of the patients with ACLF is more than 50%, and the incidence of the ACLF is increasing year by year [4]. At present, liver transplantation is a major method in clinic for ACLF treatment, while the shortages of donor livers limit the efficiency of the treatment for the patients [5,6].…”