title: ZNF143 transcription factor mediates cell survival through upregulation of the GPX1 activity in the mitochondrial respiratory dysfunction.
abstract: Mitochondrial respiratory dysfunction has intimate relationship with redox regulation. The key mechanism about how the mitochondrial respiration-defective cells survive oxidative stress is still elusive. Here, we report that transcription factor zinc-finger protein 143 (ZNF143) expression and glutathione peroxidase (GPX) activity are markedly increased in the mitochondrial respiratory-defective cells induced by dominant-negative DNA polymerase γ (POLGdn). In this work, investigation of the cellular antioxidant glutathione (GSH) and enzyme GPX activity in the mitochondrial dysfunction revealed the presence of an increased synthesis of GSH through the activation of GCLC (glutamate-cysteine ligase catalytic subunit) and GCLM (glutamate-cysteine ligase regulatory subunit) gene expression, and also a positive upregulation of glutathione peroxidase 1 (GPX1) activity by the transcription factor ZNF143. Significant increase in gene expression of SepSecS, the key enzyme responsible for selenocysteine transfer RNA (tRNA) synthesis, further confirmed the activation of the selenocysteine synthesis pathway. By using both GPX1 and ZNF143 knockdown, we provided insight into the involvement of ZNF143 in promoting GPX1 activity and protecting cells from oxidative damage and cisplatin treatment in the mitochondrial dysfunction. Furthermore, we reported the possible regulation of mitochondrial transcription factor A (TFAM) in the mitochondrial dysfunction. Our findings delineate an important antioxidant survival pathway that allows the mitochondrial-defective cells to survive oxidative stress and cisplatin treatment.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. wqlu@mdanderson.org
authors.forename: W
authors.initials: W
authors.lastname: Lu
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: P
authors.initials: P
authors.lastname: Huang
mesh_terms: D002460:Cell Line; D019069:Cell Respiration; D002470:Cell Survival; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000094765:Glutathione Peroxidase GPX1
chemical_list: D015534:Trans-Activators; C114253:ZNF143 protein, human; D005979:Glutathione Peroxidase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D005978:Glutathione; D010100:Oxygen; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human