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

  • Nat Commun. 2023 Nov 18;14(1):7527. doi: 10.1038/s41467-023-43439-0.
Yankun Zhang  1 ,  Yuchen Fan  2 ,  Huili Hu  3 ,  Xiaohui Zhang  3 ,  Zehua Wang  1 ,  Zhuanchang Wu  1 ,  Liyuan Wang  1 ,  Xiangguo Yu  1 ,  Xiaojia Song  1 ,  Peng Xiang  1 ,  Xiaodong Zhang  1 ,  Tixiao Wang  1 ,  Siyu Tan  1 ,  Chunyang Li  1  4 ,  Lifen Gao  1 ,  Xiaohong Liang  1 ,  Shuijie Li  5 ,  Nailin Li  6 ,  Xuetian Yue  7  8 ,  Chunhong Ma  9
Affiliations
  • 1. Key Laboratory for Experimental Teratology of Ministry of Education, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, China.
  • 2. Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China.
  • 3. Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Shandong University, Jinan, China.
  • 4. Department of Histology and Embryology, School of Basic Medical Sciences, Shandong University, Jinan, China.
  • 5. College of Pharmacy, Harbin Medical University, Harbin, China.
  • 6. Department of Medicine-Solna, Cardiovascular Medicine Unit, Karolinska Institute, Stockholm, Sweden.
  • 7. Key Laboratory for Experimental Teratology of Ministry of Education, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, China. [email protected].
  • 8. Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected].
  • 9. Key Laboratory for Experimental Teratology of Ministry of Education, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, China. [email protected].
PMID: 37980429 DOI: 10.1038/s41467-023-43439-0
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.

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