Genetic disruption of mitochondrial dynamics and stasis leads to liver injury and tumorigenesis
Xiaowen Ma, Xiaoli Wei, Mengwei Niu, Chen Zhang, Zheyun Peng, Wanqing Liu, Junrong Yan, Xiaoyang Su, Lichun Ma, Shaolei Lu, Wei Cui, Hiromi Sesaki, Wei-Xing Zong, Hong-Min Ni, Wen-Xing Ding
Xiaowen Ma, Xiaoli Wei, Mengwei Niu, Chen Zhang, Zheyun Peng, Wanqing Liu, Junrong Yan, Xiaoyang Su, Lichun Ma, Shaolei Lu, Wei Cui, Hiromi Sesaki, Wei-Xing Zong, Hong-Min Ni, Wen-Xing Ding
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Research Article Cell biology Hepatology

Genetic disruption of mitochondrial dynamics and stasis leads to liver injury and tumorigenesis

Abstract

Mitochondrial fission is mediated by dynamin-related protein 1 (gene name DNM1L) and fusion by mitofusins (MFN1 and MFN2) and optic atrophy 1. The role of mitochondrial dynamics in liver disease and cancer remains poorly understood. We analyzed single, double, and triple liver-specific KO mice lacking mitochondrial fission and fusion proteins using systematic analyses of mitochondrial morphology, untargeted metabolomics, RNA-seq, hydrodynamic tail vein injection of oncogenes, and human hepatocellular carcinoma samples. Liver-specific Dnm1l-KO (L-Dnm1l–KO) mice showed increased alanine aminotransferase levels and hepatic fibrosis, with spontaneous liver tumors developing by 12 to 18 months of age. L-Mfn1– and L-Mfn2–KO mice showed no significant liver damage or tumor development, although a small percentage of L-Mfn1, Mfn2 double KO mice developed tumors. Dnm1l, Mfn1, and Mfn2 triple KO (TKO) mice experienced significantly reduced liver injury and fibrosis, along with decreased spontaneous and oncogene-induced tumorigenesis. L-Dnm1l–KO mice showed increased activation of the cGAS/STING/interferon pathway and pyrimidine metabolism, which were significantly normalized in TKO mice. Deletion of hepatic cGas reduced both basal and oncogene-induced liver injury and tumor development in L-Dnm1l–KO mice. These findings indicate that mitochondrial dynamics are crucial for maintaining hepatic pyrimidine metabolism and regulating the cGAS/STING-mediated immune response to prevent liver tumorigenesis.

Authors

Xiaowen Ma, Xiaoli Wei, Mengwei Niu, Chen Zhang, Zheyun Peng, Wanqing Liu, Junrong Yan, Xiaoyang Su, Lichun Ma, Shaolei Lu, Wei Cui, Hiromi Sesaki, Wei-Xing Zong, Hong-Min Ni, Wen-Xing Ding

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Figure 4

Loss of liver Dnm1l activates the cGAS/STING/interferon pathway and promotes tumor microenvironment transformation, blunted in TKO mice.

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Loss of liver Dnm1l activates the cGAS/STING/interferon pathway and prom...
(A) PCA of RNA-seq dataset. (B) Volcano plot of RNA-seq dataset. (C) The top up- and downregulated pathways identified by Ingenuity Pathway Analysis from RNA-seq dataset of indicated mouse liver tissues. (D) Heatmap of genes involved in the interferon and cGAS/STING pathways from the RNA-seq dataset. (E and F) Representative IHC staining of IRF7 in 2M mouse liver. At least 5 fields were quantified from each mouse (n = 3 mice). Scale bars: 100 μm. All results are expressed as mean ± SD. ***P < 0.001; 1-way ANOVA analysis with Bonferroni’s post hoc test.