ZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury.
Yankun ZhangYuchen FanHuili HuXiaohui ZhangZehua WangZhuanchang WuLiyuan WangXiangguo YuXiaojia SongPeng XiangXiaodong ZhangTixiao WangSiyu TanChunyang LiLifen GaoXiaohong LiangShuijie LiChunyang LiXuetian YueChunhong MaPublished in: Nature communications (2023)
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.
Keyphrases
- liver injury
- drug induced
- oxidative stress
- poor prognosis
- liver failure
- skeletal muscle
- transcription factor
- gene expression
- type diabetes
- respiratory failure
- emergency department
- metabolic syndrome
- risk assessment
- long non coding rna
- insulin resistance
- dna methylation
- adipose tissue
- binding protein
- aortic dissection
- wild type
- liver fibrosis
- big data
- artificial intelligence
- data analysis
- wound healing