Human AP endonuclease/redox factor APE1/ref-1 modulates mitochondrial function after oxidative stress by regulating the transcriptional activity of NRF1

Mengxia Li; Carlo Vascotto; Shangcheng Xu; Nan Dai; Yi Qing; Zhaoyang Zhong; Gianluca Tell; Dong Wang

doi:10.1016/j.freeradbiomed.2012.04.002

Human AP endonuclease/redox factor APE1/ref-1 modulates mitochondrial function after oxidative stress by regulating the transcriptional activity of NRF1

Free Radic Biol Med. 2012 Jul 15;53(2):237-48. doi: 10.1016/j.freeradbiomed.2012.04.002. Epub 2012 May 11.

Authors

Mengxia Li¹, Carlo Vascotto, Shangcheng Xu, Nan Dai, Yi Qing, Zhaoyang Zhong, Gianluca Tell, Dong Wang

Affiliation

¹ Cancer Center and Department of Pathology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People's Republic of China.

PMID: 22580151
DOI: 10.1016/j.freeradbiomed.2012.04.002

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Nucleus / genetics
Cell Nucleus / metabolism*
Cell Respiration / drug effects
DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics
DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Electron Transport Complex IV / genetics
Electron Transport Complex IV / metabolism
Gene Expression / drug effects
Gene Knockdown Techniques
HeLa Cells
Humans
Mitochondria / drug effects
Mitochondria / genetics
Mitochondria / metabolism*
Mitochondrial Membrane Transport Proteins / genetics
Mitochondrial Membrane Transport Proteins / metabolism
Mitochondrial Precursor Protein Import Complex Proteins
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism
NF-E2-Related Factor 1 / genetics
NF-E2-Related Factor 1 / metabolism*
Oxidative Stress
Signal Transduction / drug effects
Transcription Factors / genetics
Transcription Factors / metabolism
Transcription, Genetic / drug effects
Transcriptional Activation / drug effects
Transfection
tert-Butylhydroperoxide / pharmacology

Substances

COX6c protein, human
DNA-Binding Proteins
Mitochondrial Membrane Transport Proteins
Mitochondrial Precursor Protein Import Complex Proteins
Mitochondrial Proteins
NF-E2-Related Factor 1
NFE2L1 protein, human
TFAM protein, human
TOMM22 protein, human
Transcription Factors
tert-Butylhydroperoxide
Electron Transport Complex IV
APEX1 protein, human
DNA-(Apurinic or Apyrimidinic Site) Lyase