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Title: The aryl hydrocarbon receptor interacts with ATP5{alpha}1, a subunit of the ATP synthase complex, and modulates mitochondrial function

Abstract

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 ATP5{alpha}1, 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:ATP5{alpha}1 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 tomore » the mitochondria and contributes to the organelle's homeostasis. - Highlights: > The AHR interacts with the mitochondrial protein, ATP5{alpha}1. > Cell fractionation experiments show that the AHR can be found in the mitochondria. > TCDD-exposure induces a hyperpolarization of the mitochondrial inner membrane. > The hyperpolarization is AHR-dependent. > The hyperpolarization occurs without altering ATP levels within the cell.« less

Authors:
;  [1];  [2];  [3]; ;  [1];  [4];  [2];  [5];  [1];  [2];  [2]
  1. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824-1319 (United States)
  2. (United States)
  3. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1319 (United States)
  4. Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1319 (United States)
  5. The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States)
Publication Date:
OSTI Identifier:
21587809
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 254; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2011.05.004; PII: S0041-008X(11)00173-6; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AFFINITY; ATP; DIOXIN; FRACTIONATION; HOMEOSTASIS; HYDROCARBONS; INTERACTIONS; LIGANDS; MAMMALS; MASS SPECTROSCOPY; MEMBRANES; MITOCHONDRIA; RECEPTORS; TOXICITY; TRANSCRIPTION FACTORS; ANIMALS; CELL CONSTITUENTS; HETEROCYCLIC COMPOUNDS; MEMBRANE PROTEINS; NUCLEOTIDES; ORGANIC COMPOUNDS; ORGANIC OXYGEN COMPOUNDS; PROTEINS; SEPARATION PROCESSES; SPECTROSCOPY; VERTEBRATES

Citation Formats

Tappenden, Dorothy M., Lynn, Scott G., Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1319, Crawford, Robert B., Lee, KangAe, Vengellur, Ajith, Kaminski, Norbert E., Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1319, Thomas, Russell S., LaPres, John J., E-mail: lapres@msu.edu, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1319, and Center for Mitochondrial Science and Medicine, Michigan State University, East Lansing, MI 48824-1319. The aryl hydrocarbon receptor interacts with ATP5{alpha}1, a subunit of the ATP synthase complex, and modulates mitochondrial function. United States: N. p., 2011. Web. doi:10.1016/j.taap.2011.05.004.
Tappenden, Dorothy M., Lynn, Scott G., Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1319, Crawford, Robert B., Lee, KangAe, Vengellur, Ajith, Kaminski, Norbert E., Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1319, Thomas, Russell S., LaPres, John J., E-mail: lapres@msu.edu, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1319, & Center for Mitochondrial Science and Medicine, Michigan State University, East Lansing, MI 48824-1319. The aryl hydrocarbon receptor interacts with ATP5{alpha}1, a subunit of the ATP synthase complex, and modulates mitochondrial function. United States. doi:10.1016/j.taap.2011.05.004.
Tappenden, Dorothy M., Lynn, Scott G., Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1319, Crawford, Robert B., Lee, KangAe, Vengellur, Ajith, Kaminski, Norbert E., Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1319, Thomas, Russell S., LaPres, John J., E-mail: lapres@msu.edu, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1319, and Center for Mitochondrial Science and Medicine, Michigan State University, East Lansing, MI 48824-1319. Mon . "The aryl hydrocarbon receptor interacts with ATP5{alpha}1, a subunit of the ATP synthase complex, and modulates mitochondrial function". United States. doi:10.1016/j.taap.2011.05.004.
@article{osti_21587809,
title = {The aryl hydrocarbon receptor interacts with ATP5{alpha}1, a subunit of the ATP synthase complex, and modulates mitochondrial function},
author = {Tappenden, Dorothy M. and Lynn, Scott G. and Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1319 and Crawford, Robert B. and Lee, KangAe and Vengellur, Ajith and Kaminski, Norbert E. and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1319 and Thomas, Russell S. and LaPres, John J., E-mail: lapres@msu.edu and Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1319 and Center for Mitochondrial Science and Medicine, Michigan State University, East Lansing, MI 48824-1319},
abstractNote = {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 ATP5{alpha}1, 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:ATP5{alpha}1 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. - Highlights: > The AHR interacts with the mitochondrial protein, ATP5{alpha}1. > Cell fractionation experiments show that the AHR can be found in the mitochondria. > TCDD-exposure induces a hyperpolarization of the mitochondrial inner membrane. > The hyperpolarization is AHR-dependent. > The hyperpolarization occurs without altering ATP levels within the cell.},
doi = {10.1016/j.taap.2011.05.004},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 254,
place = {United States},
year = {2011},
month = {8}
}