scholarly journals Mitochondrial uncouplers with an extraordinary dynamic range

2007 ◽  
Vol 407 (1) ◽  
pp. 129-140 ◽  
Author(s):  
Phing-How Lou ◽  
Birgit S. Hansen ◽  
Preben H. Olsen ◽  
Søren Tullin ◽  
Michael P. Murphy ◽  
...  
Keyword(s):  
Dynamic Range ◽  
Adenine Nucleotide ◽  
Weak Acid ◽  
Butylated Hydroxytoluene ◽  
Adenine Nucleotide Translocase ◽  
Covalent Attachment ◽  
Intact Cells ◽  
Starting Point ◽  
Mitochondrial Uncouplers ◽  
Affinity Interaction

We have discovered that some weak uncouplers (typified by butylated hydroxytoluene) have a dynamic range of more than 106in vitro: the concentration giving measurable uncoupling is less than one millionth of the concentration causing full uncoupling. They achieve this through a high-affinity interaction with the mitochondrial adenine nucleotide translocase that causes significant but limited uncoupling at extremely low uncoupler concentrations, together with more conventional uncoupling at much higher concentrations. Uncoupling at the translocase is not by a conventional weak acid/anion cycling mechanism since it is also caused by substituted triphenylphosphonium molecules, which are not anionic and cannot protonate. Covalent attachment of the uncoupler to a mitochondrially targeted hydrophobic cation sensitizes it to membrane potential, giving a small additional effect. The wide dynamic range of these uncouplers in isolated mitochondria and intact cells reveals a novel allosteric activation of proton transport through the adenine nucleotide translocase and provides a promising starting point for designing safer uncouplers for obesity therapy.

scholarly journals Recruitment of NF-κB into Mitochondria Is Involved in Adenine Nucleotide Translocase 1 (ANT1)-induced Apoptosis

2004 ◽  
Vol 279 (37) ◽  
pp. 38415-38423 ◽  
Author(s):  
Monica Zamora ◽  
Claudia Meroño ◽  
Octavi Viñas ◽  
Teresa Mampel
Keyword(s):  
Adenine Nucleotide ◽  
Adenine Nucleotide Translocase ◽  
Induced Apoptosis

scholarly journals An isoform shift in the cardiac adenine nucleotide translocase expression alters the kinetic properties of the carrier in dilated cardiomyopathy

2005 ◽  
Vol 8 (1) ◽  
pp. 81-89 ◽  
Author(s):  
Andrea Dörner ◽  
Stefanie Giessen ◽  
Regina Gaub ◽  
Helga Große Siestrup ◽  
Peter L. Schwimmbeck ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Adenine Nucleotide ◽  
Adenine Nucleotide Translocase ◽  
Kinetic Properties

scholarly journals Adenine nucleotide translocase regulates airway epithelial metabolism, surface hydration and ciliary function

2021 ◽  
Vol 134 (4) ◽  
pp. jcs257162 ◽  
Author(s):  
Corrine R. Kliment ◽  
Jennifer M. K. Nguyen ◽  
Mary Jane Kaltreider ◽  
YaWen Lu ◽  
Steven M. Claypool ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Adenine Nucleotide ◽  
Airway Epithelial Cells ◽  
Adenine Nucleotide Translocase ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Ciliary Function ◽  
Transporter Family ◽  
Surface Hydration

ABSTRACTAirway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive pulmonary disease (COPD), which is impacted by cigarette smoking and has no therapeutic options. We utilized a high-copy cDNA library genetic selection approach in the amoeba Dictyostelium discoideum to identify genetic protectors to cigarette smoke. Members of the mitochondrial ADP/ATP transporter family adenine nucleotide translocase (ANT) are protective against cigarette smoke in Dictyostelium and human bronchial epithelial cells. Gene expression of ANT2 is reduced in lung tissue from COPD patients and in a mouse smoking model, and overexpression of ANT1 and ANT2 resulted in enhanced oxidative respiration and ATP flux. In addition to the presence of ANT proteins in the mitochondria, they reside at the plasma membrane in airway epithelial cells and regulate airway homeostasis. ANT2 overexpression stimulates airway surface hydration by ATP and maintains ciliary beating after exposure to cigarette smoke, both of which are key functions of the airway. Our study highlights a potential for upregulation of ANT proteins and/or of their agonists in the protection from dysfunctional mitochondrial metabolism, airway hydration and ciliary motility in COPD.This article has an associated First Person interview with the first author of the paper.

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