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Mertk+ Liver Sinusoidal Endothelial Cells Negatively Regulate PINK1 Related Mitophagy and Accelerate MASH
Yu-Xuan Gao1, Zhong Weng2,3, Long Tang2,3
1Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Background:
Mer tyrosine kinase (Mertk) regulating mitochondrial function of liver sinusoidal endothelial cells (LSECs) in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear.
Methods:
Mertk/p-Mertk, PINK1, and ERK/p-ERK expression in steatotic LSECs and livers of MASH mice were studied. Mitochondrial functions were assessed via immunofluorescence, Western blot, and qPCR. C-Kit+-bone marrow cells (BMCs)sh-Mertk were bone marrow transplanted (BMT) to MASH mice to evaluate its effect.
Results:
Ov-Mertk would markedly stimulate ERK, and ERK further suppress downstream PINK1. Higher levels of Mertk/p-Mertk and lower levels of PINK1 were confirmed in steatotic LSECs and MASH mice livers. Steatotic LSECssh-Mertk exhibited intact mitophagy, integral mitochondrial membrane potential, reduced reactive oxygen productions and upregulation of the PINK1 pathway. BMT of C-Kit+-BMCssh-Mertk could equivalently protect mitochondrial functions and ameliorate lipid accumulation in MASH mice.
Conclusion:
Mertk negatively regulates PINK1-mediated mitophagy in LSECs through the p-ERK signaling pathway, thereby accelerating MASH progression. Therefore, LSECs deficient of Mertk should be a novel therapy for reversing PINK1-related mitophagy and MASH.
Insights
Mer tyrosine kinase (Mertk) negatively impacts mitophagy in liver cells, worsening metabolic dysfunction-associated steatohepatitis (MASH). Mertk deficiency in liver sinusoidal endothelial cells (LSECs) offers a potential therapy for MASH by restoring mitophagy.
Area of Science:
- Hepatology and cell biology
- Mitochondrial research
- Metabolic disease mechanisms
Background:
- Mer tyrosine kinase (Mertk) role in liver sinusoidal endothelial cell (LSEC) mitochondrial function in metabolic dysfunction-associated steatohepatitis (MASH) is not well understood.
- Understanding Mertk's regulation of mitochondrial dynamics is crucial for MASH pathogenesis.
Purpose of the Study:
- To investigate the role of Mertk in regulating LSEC mitochondrial function and mitophagy in MASH.
- To explore the potential of targeting Mertk for MASH therapy.
Main Methods:
- Assessed Mertk, PINK1, and ERK signaling pathways in steatotic LSECs and MASH mouse livers using Western blot and qPCR.
- Evaluated mitochondrial function, mitophagy, and reactive oxygen species production in LSECs.
- Utilized bone marrow transplantation of Mertk-deficient C-Kit+ cells in MASH mice.
Main Results:
- Mertk activation stimulated ERK, which suppressed PINK1, leading to higher Mertk/p-Mertk and lower PINK1 levels in MASH livers.
- Mertk-deficient LSECs showed improved mitophagy, mitochondrial membrane potential, reduced ROS, and PINK1 pathway upregulation.
- Bone marrow transplantation of Mertk-deficient cells ameliorated lipid accumulation and protected mitochondrial function in MASH mice.
Conclusions:
- Mertk negatively regulates PINK1-mediated mitophagy in LSECs via the p-ERK pathway, exacerbating MASH.
- LSECs with Mertk deficiency represent a potential therapeutic strategy for MASH by restoring mitophagy.
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