Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice

Lixiang Wang,Yoshinori Moriyama,Yuki Hanada,Masatoshi Nomura,Xin Li,Ken Yamamoto,Nao Hasuzawa

doi:10.1038/s42003-021-02413-6

Abstract

Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

Highlights

Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics
LPS administration increased messenger RNA levels of tumor necrosis factor alpha (Tnfa), interleukin 6 (Il6), interleukin 1 beta (Il1b), interferon beta 1 (Ifnb1), monocyte chemoattractant protein-1 (Mcp1), and the NLR family pyrin domain containing 3 (Nlrp3), which peaked at 1 h in the liver (Supplementary Fig. 1a)
TNF, IL-6, interleukin 10 (IL-10) and MCP1 levels peaked at 1 h, IL-1β levels peaked at 4 h, and interferon gamma (IFN-γ) levels peaked at 8 h (Supplementary Fig. 1b)

Summary

Introduction

Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. This study indicates that Drp[1] defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo. We reported that a mitochondrial fission defect in liver-specific Drp1-knockout (Drp1LiKO) mice, which demonstrate ER stresspromoted fibroblast growth factor 21 expression, subsequently functions as a metabolic regulator with anti-obesity and antidiabetic effects. Our previous studies have reported that Drp[1] disruption in the liver changes the expression of genes involved in the immune system in the liver. We hypothesized that Drp[1] deficiency-induced mitochondrial fission defects directly lead to liver disease development. Our study indicated that Drp[1] defect-induced liver inflammation progression, which will provide insight into the role of Drp[1] in liver function and acute liver injury

Methods

Results

Conclusion