Transcription factor NF-kappa B represses ANT1 transcription and leads to mitochondrial dysfunctions

Sci Rep. 2017 Mar 20;7:44708. doi: 10.1038/srep44708.

Abstract

Mitochondria are intracellular organelles involved in cell survival and death, and dysfunctions of mitochondria are related to neurodegenerative diseases. As the most abundant protein in the mitochondrial inner membrane, adenine nucleotide translocator 1 (ANT1) plays a critical role in mitochondrial function, including the exchange of adenosine triphosphate/adenosine diphosphate (ATP/ADP) in mitochondria, basal proton leak and mitochondrial permeability transition pore (mPTP). Here, we show that ANT1 transcription is regulated by transcription factor NF-kappa B (NF-κB). NF-κB is bound to two NF-κB responsive elements (NREs) located at +1 to +20 bp and +41 to +61 bp in the ANT1 promoter. An NF-κB signalling stimulator, tumour necrosis factor alpha (TNFα), suppresses ANT1 mRNA and protein expression. Activation of NF-κB by TNFα impairs ATP/ADP exchange and decreases ATP production in mitochondria. Activation of NF-κB by TNFα decreases calcium induced mPTP opening, elevates mitochondrial potential and increases reactive oxygen species (ROS) production in both T98G human glioblastoma cells and rat cortical neurons. These results demonstrate that NF-κB signalling may repress ANT1 gene transcription and impair mitochondrial functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine Nucleotide Translocator 1 / genetics*
  • Adenine Nucleotide Translocator 1 / metabolism
  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Base Sequence
  • Calcium / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Potential, Mitochondrial
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic / genetics
  • Reactive Oxygen Species / metabolism
  • Response Elements / genetics
  • Transcription, Genetic*

Substances

  • Adenine Nucleotide Translocator 1
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • NF-kappa B
  • Reactive Oxygen Species
  • SLC25A4 protein, human
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Calcium