title: Human AP endonuclease/redox factor APE1/ref-1 modulates mitochondrial function after oxidative stress by regulating the transcriptional activity of NRF1.
abstract: Maintenance of mitochondrial functionality largely depends on nuclear transcription because most mitochondrial proteins are encoded by the nuclear genome and transported to the mitochondria. Nuclear respiration factor 1 (NRF1) plays a crucial role in regulating the expression of a broad range of mitochondrial genes in the nucleus in response to cellular oxidative stress. However, little is known about the redox regulatory mechanism of the transcriptional activity of NRF1. In this study, we show that the human apurinic/apyrimidinic endonuclease/redox factor (APE1/Ref-1) is involved in mitochondrial function regulation by modulating the DNA-binding activity of NRF1. Our results show that both APE1 expression level and its redox activity are essential for maintenance of the mitochondrial function after tert-butylhydroperoxide-induced oxidative stress. Upon knocking down or redox mutation of APE1, NRF1 DNA-binding activity was impaired and, consequently, the expression of its downstream genes, including Tfam, Cox6c, and Tomm22, was significantly reduced. NRF1 knockdown blocked the restoration of mitochondrial function by APE1 overexpression, which further suggests APE1 regulates mitochondrial function through an NRF1-dependent pathway. Taken together, our results reveal APE1 as a new coactivator of NRF1, which highlights an additional regulatory role of APE1 in maintenance of mitochondrial functionality.
authors.affiliation: Cancer Center and Department of Pathology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China.
authors.forename: Mengxia
authors.initials: M
authors.lastname: Li
authors.forename: Carlo
authors.initials: C
authors.lastname: Vascotto
authors.forename: Shangcheng
authors.initials: S
authors.lastname: Xu
authors.forename: Nan
authors.initials: N
authors.lastname: Dai
authors.forename: Yi
authors.initials: Y
authors.lastname: Qing
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Zhong
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tell
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
mesh_terms: D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D019069:Cell Respiration / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D051265:NF-E2-Related Factor 1 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: C404795:COX6c protein, human; D004268:DNA-Binding Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D051265:NF-E2-Related Factor 1; C088357:NFE2L1 protein, human; C499631:TFAM protein, human; C489971:TOMM22 protein, human; D014157:Transcription Factors; D020122:tert-Butylhydroperoxide; D003576:Electron Transport Complex IV; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase