The aryl hydrocarbon receptor interacts with ATP5α1, a subunit of the ATP synthase complex, and modulates mitochondrial function

Toxicol Appl Pharmacol. 2011 Aug 1;254(3):299-310. doi: 10.1016/j.taap.2011.05.004. Epub 2011 May 12.


Dioxins, including 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), produce a wide range of toxic effects in mammals. Most, if not all, of these toxic effects are regulated by the aryl hydrocarbon receptor (AHR). The AHR is a ligand activated transcription factor that has been shown to interact with numerous proteins capable of influencing the receptor's function. The ability of secondary proteins to alter AHR-mediated transcriptional events, a necessary step for toxicity, led us to determine whether additional interacting proteins could be identified. To this end, we have employed tandem affinity purification (TAP) of the AHR in Hepa1c1c7 cells. TAP of the AHR, followed by mass spectrometry (MS) identified ATP5α1, a subunit of the ATP synthase complex, as a strong AHR interactor in the absence of ligand. The interaction was lost upon exposure to TCDD. The association was confirmed by co-immunoprecipitation in multiple cell lines. In addition, cell fractionation experiments showed that a fraction of the AHR is found in the mitochondria. To ascribe a potential functional role to the AHR:ATP5α1 interaction, TCDD was shown to induce a hyperpolarization of the mitochondrial membrane in an AHR-dependent and transcription-independent manner. These results suggest that a fraction of the total cellular AHR pool is localized to the mitochondria and contributes to the organelle's homeostasis.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Synthetase Complexes / metabolism
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Homeostasis / physiology
  • Mice
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / physiology*
  • Mitochondrial Proteins / metabolism*
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Molecular Sequence Data
  • Oxidative Phosphorylation Coupling Factors / metabolism*
  • Polychlorinated Dibenzodioxins / metabolism
  • Polychlorinated Dibenzodioxins / toxicity
  • Protein Binding / physiology
  • Protein Subunits / metabolism
  • Receptors, Aryl Hydrocarbon / metabolism*


  • Mitochondrial Proteins
  • Oxidative Phosphorylation Coupling Factors
  • Polychlorinated Dibenzodioxins
  • Protein Subunits
  • Receptors, Aryl Hydrocarbon
  • ATP Synthetase Complexes
  • F(6) ATPase
  • Mitochondrial Proton-Translocating ATPases