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  3. IP3R1-mediated MAMs formation contributes to mechanical trauma-induced hepatic injury and the protective effect of melatonin

IP3R1-mediated MAMs formation contributes to mechanical trauma-induced hepatic injury and the protective effect of melatonin

  • Cell Mol Biol Lett. 2024 Feb 2;29(1):22. doi: 10.1186/s11658-023-00509-x.
Rui Shi # 1 2 3,  Zhenhua Liu # 2,  Huan Yue # 2 4,  Man Li 2 4,  Simin Liu 1,  Dema De 1 3,  Runjing Li 1 3,  Yunan Chen 1 3,  Shuli Cheng 5,  Xiaoming Gu 2,  Min Jia 2,  Jun Li 2,  Juan Li 2,  Shumiao Zhang 2,  Na Feng 2,  Rong Fan 2,  Feng Fu 2,  Yali Liu 6,  Mingge Ding 7 8,  Jianming Pei 9
Affiliations

Affiliations

  • 1 Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, China.
  • 3 Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education, Xi'an, China.
  • 4 School of Life Science, Northwest University, Xi'an, China.
  • 5 The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Laboratory Center of Stomatology, Department of Orthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
  • 6 Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, China. yaliliu@fmmu.edu.cn.
  • 7 Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. dingmingge@xjtu.edu.cn.
  • 8 The Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Laboratory Center of Stomatology, Department of Orthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, China. dingmingge@xjtu.edu.cn.
  • 9 Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, China. jmpei8@fmmu.edu.cn.
  • # Contributed equally.
PMID: 38308199 DOI: 10.1186/s11658-023-00509-x
Abstract

Introduction: There is a high morbidity and mortality rate in mechanical trauma (MT)-induced hepatic injury. Currently, the molecular mechanisms underlying liver MT are largely unclear. Exploring the underlying mechanisms and developing safe and effective medicines to alleviate MT-induced hepatic injury is an urgent requirement. The aim of this study was to reveal the role of mitochondria-associated ER membranes (MAMs) in post-traumatic liver injury, and ascertain whether melatonin protects against MT-induced hepatic injury by regulating MAMs.

Methods: Hepatic mechanical injury was established in Sprague-Dawley rats and primary hepatocytes. A variety of experimental methods were employed to assess the effects of melatonin on hepatic injury, Apoptosis, MAMs formation, mitochondrial function and signaling pathways.

Results: Significant increase of IP3R1 expression and MAMs formation were observed in MT-induced hepatic injury. Melatonin treatment at the dose of 30 mg/kg inhibited IP3R1-mediated MAMs and attenuated MT-induced liver injury in vivo. In vitro, primary hepatocytes cultured in 20% trauma serum (TS) for 12 h showed upregulated IP3R1 expression, increased MAMs formation and cell injury, which were suppressed by melatonin (100 μmol/L) treatment. Consequently, melatonin suppressed mitochondrial calcium overload, increased mitochondrial membrane potential and improved mitochondrial function under traumatic condition. Melatonin's inhibitory effects on MAMs formation and mitochondrial calcium overload were blunted when IP3R1 was overexpressed. Mechanistically, melatonin bound to its receptor (MR) and increased the expression of phosphorylated ERK1/2, which interacted with FoxO1 and inhibited the activation of FoxO1 that bound to the IP3R1 promoter to inhibit MAMs formation.

Conclusion: Melatonin prevents the formation of MAMs via the MR-ERK1/2-FoxO1-IP3R1 pathway, thereby alleviating the development of MT-induced liver injury. Melatonin-modulated MAMs may be a promising therapeutic therapy for traumatic hepatic injury.

Keywords

ERK1/2; FoxO1; IP3R1; MAMs; Mechanical trauma; Melatonin.

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