DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy

作     者：Hao Zhou Pingjun Zhu Jin Wang Sam Toan Jun Ren 

作者机构：Chinese PLA General HospitalMedical School of Chinese PLA100853BeijingChina Center for Cardiovascular Research and Alternative MedicineUniversity of Wyoming College of Health SciencesLaramieWY82071USA Department of Chemical EngineeringUniversity of Minnesota-DuluthDuluthMN55812USA 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2019年第4卷第1期

页      面：161-172页

核心收录：

学科分类：07[理学] 070202[理学-粒子物理与原子核物理] 0702[理学-物理学] 

基　　金：This work was supported in part by the National Key R&D Program of China(2017YFA0506000) China Postdoctoral Science Foundation(2019TQ0128) the NSFC(81900252,81770261,81900254 and 91749128) 

主　　题：process. alcohol activation 

摘      要：DNA-dependent protein kinase catalytic subunit(DNA-PKcs)is a novel housekeeper of hepatic mitochondrial homeostasis outside the DNA repair *** this study,DNA-PKcs was upregulated in the livers of mice that were exposed to alcohol;the expression of DNA-PKcs positively correlated with hepatic steatosis,fibrosis,apoptosis,and mitochondrial *** studies revealed that liver-specific DNA-PKcs knockout(DNA-PKcsLKO)mice were protected from chronic ethanol-induced liver injury and mitochondrial *** investigations established that DNA-PKcs promoted p53 activation,which elevated dynamin-related protein 1(Drp1)-related mitochondrial fission but repressed FUN14 domain containing 1(FUNDC1)-required *** fission and defective mitophagy triggered mtDNA damage,mitochondrial respiratory inhibition,mROS overproduction,cardiolipin oxidation,redox imbalance,calcium overload,and hepatic mitochondrial *** contrast,the deletion of DNA-PKcs rescued these phenotypic alterations,which alleviated the susceptibility of hepatocytes to alcohol-induced ***,we also showed that orphan nuclear receptor subfamily 4 group A member 1(NR4A1)was the upstream signal for DNA-PKcs activation and that the genetic ablation of NR4A1 ameliorated the progression of alcohol-related liver disease(ARLD);these results were similar to those obtained in DNA-PKcs knockout ***,our results identified the NR4A1/DNA-PKcs/p53 axis as a novel signaling pathway responsible for ARLD pathogenesis that acts by activating Drp1-related mitochondrial fission and restricting FUNDC1-required *** findings have potential implications for new approaches for ARLD therapy.