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Published on: November 27, 2019
PINK1 ameliorates acute-on-chronic liver failure by inhibiting apoptosis through mTORC2/AKT signaling
Xuehong Yin1, Ran Xue2, Jing Wu1
1Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, Beijing, China.
Abstract:
Acute-on-chronic liver failure (ACLF) is a lethal syndrome with a remarkable short-term death rate. Even worse, effective internal medicine therapies are currently lacking. Increasing evidence indicates apoptosis plays a critical role in the progression of liver failure. PINK1 has an essential function in maintaining cell survival. However, the role and underlying mechanism of PINK1 in apoptosis in ACLF are incompletely understood. Herein, our team discovered that PINK1 remarkably improved ACLF, featured by a reduction in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and an amelioration in the gross and microscopy histopathology appearance of hepatic tissues. Meanwhile, PINK1 affected cleaved caspase-3 expression via mTORC2/AKT, and this effect was eliminated after further intervention with Rictor or AKT. Overall, these findings indicate that PINK1 participates in the regulation of multiple biological functions, including hepatic cell growth and apoptosis in ACLF via the mTORC2/AKT signaling pathway. The present research offers a solid theory-wise foundation for the clinic applications of PINK1 as a valid target for ACLF treatment to reverse or postpone the development of ACLF.
Insights
PINK1 protein significantly improves acute-on-chronic liver failure (ACLF) by reducing liver damage markers and regulating apoptosis. This suggests PINK1 is a promising therapeutic target for ACLF treatment.
Area of Science:
- Hepatology
- Molecular Biology
- Cellular Biology
Background:
- Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome with high mortality and limited treatment options.
- Apoptosis is increasingly recognized as a key factor in the pathogenesis of liver failure.
- The role of PINK1 in ACLF-related apoptosis remains largely unknown.
Purpose of the Study:
- To investigate the therapeutic potential of PINK1 in ACLF.
- To elucidate the underlying molecular mechanisms of PINK1 in regulating apoptosis in ACLF.
Main Methods:
- Assessment of ACLF markers (AST, ALT) and liver histopathology.
- Investigation of PINK1's effect on cleaved caspase-3 expression.
- Analysis of the involvement of the mTORC2/AKT signaling pathway.
Main Results:
- PINK1 administration significantly ameliorated ACLF, evidenced by reduced AST and ALT levels and improved liver tissue appearance.
- PINK1 modulated cleaved caspase-3 expression through the mTORC2/AKT pathway.
- Inhibition of Rictor or AKT abolished the effects of PINK1 on cleaved caspase-3.
Conclusions:
- PINK1 plays a crucial role in regulating hepatic cell survival and apoptosis in ACLF.
- The protective effects of PINK1 in ACLF are mediated via the mTORC2/AKT signaling pathway.
- PINK1 represents a potential therapeutic target for managing ACLF.
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