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ZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury

Author

Listed:
  • Yankun Zhang

    (Cheeloo Medical College of Shandong University)

  • Yuchen Fan

    (Qilu Hospital of Shandong University)

  • Huili Hu

    (Shandong University)

  • Xiaohui Zhang

    (Shandong University)

  • Zehua Wang

    (Cheeloo Medical College of Shandong University)

  • Zhuanchang Wu

    (Cheeloo Medical College of Shandong University)

  • Liyuan Wang

    (Cheeloo Medical College of Shandong University)

  • Xiangguo Yu

    (Cheeloo Medical College of Shandong University)

  • Xiaojia Song

    (Cheeloo Medical College of Shandong University)

  • Peng Xiang

    (Cheeloo Medical College of Shandong University)

  • Xiaodong Zhang

    (Cheeloo Medical College of Shandong University)

  • Tixiao Wang

    (Cheeloo Medical College of Shandong University)

  • Siyu Tan

    (Cheeloo Medical College of Shandong University)

  • Chunyang Li

    (Cheeloo Medical College of Shandong University
    Shandong University)

  • Lifen Gao

    (Cheeloo Medical College of Shandong University)

  • Xiaohong Liang

    (Cheeloo Medical College of Shandong University)

  • Shuijie Li

    (Harbin Medical University)

  • Nailin Li

    (Karolinska Institute)

  • Xuetian Yue

    (Cheeloo Medical College of Shandong University
    Shandong University)

  • Chunhong Ma

    (Cheeloo Medical College of Shandong University)

Abstract

Mitochondria dysfunction contributes to acute liver injuries, and mitochondrial regulators, such as PGC-1α and MCJ, affect liver regeneration. Therefore, identification of mitochondrial modulators may pave the way for developing therapeutic strategies. Here, ZHX2 is identified as a mitochondrial regulator during acute liver injury. ZHX2 both transcriptionally inhibits expression of several mitochondrial electron transport chain genes and decreases PGC-1α stability, leading to reduction of mitochondrial mass and OXPHOS. Loss of Zhx2 promotes liver recovery by increasing mitochondrial OXPHOS in mice with partial hepatectomy or CCl4-induced liver injury, and inhibition of PGC-1α or electron transport chain abolishes these effects. Notably, ZHX2 expression is higher in liver tissues from patients with drug-induced liver injury and is negatively correlated with mitochondrial mass marker TOM20. Delivery of shRNA targeting Zhx2 effectively protects mice from CCl4-induced liver injury. Together, our data clarify ZHX2 as a negative regulator of mitochondrial OXPHOS and a potential target for developing strategies for improving liver recovery after acute injuries.

Suggested Citation

  • Yankun Zhang & Yuchen Fan & Huili Hu & Xiaohui Zhang & Zehua Wang & Zhuanchang Wu & Liyuan Wang & Xiangguo Yu & Xiaojia Song & Peng Xiang & Xiaodong Zhang & Tixiao Wang & Siyu Tan & Chunyang Li & Life, 2023. "ZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43439-0
    DOI: 10.1038/s41467-023-43439-0
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    1. Jin Zhou & Jeremy Pang & Madhulika Tripathi & Jia Pei Ho & Anissa Anindya Widjaja & Shamini Guna Shekeran & Stuart Alexander Cook & Ayako Suzuki & Anna Mae Diehl & Enrico Petretto & Brijesh Kumar Sing, 2022. "Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
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