title: ATP/ADP Turnover and Import of Glycolytic ATP into Mitochondria in Cancer Cells Is Independent of the Adenine Nucleotide Translocator.
abstract: Non-proliferating cells oxidize respiratory substrates in mitochondria to generate a protonmotive force (Δp) that drives ATP synthesis. The mitochondrial membrane potential (ΔΨ), a component of Δp, drives release of mitochondrial ATP(4-) in exchange for cytosolic ADP(3-) via the electrogenic adenine nucleotide translocator (ANT) located in the mitochondrial inner membrane, which leads to a high cytosolic ATP/ADP ratio up to >100-fold greater than matrix ATP/ADP. In rat hepatocytes, ANT inhibitors, bongkrekic acid (BA), and carboxyatractyloside (CAT), and the F1FO-ATP synthase inhibitor, oligomycin (OLIG), inhibited ureagenesis-induced respiration. However, in several cancer cell lines, OLIG but not BA and CAT inhibited respiration. In hepatocytes, respiratory inhibition did not collapse ΔΨ until OLIG, BA, or CAT was added. Similarly, in cancer cells OLIG and 2-deoxyglucose, a glycolytic inhibitor, depolarized mitochondria after respiratory inhibition, which showed that mitochondrial hydrolysis of glycolytic ATP maintained ΔΨ in the absence of respiration in all cell types studied. However in cancer cells, BA, CAT, and knockdown of the major ANT isoforms, ANT2 and ANT3, did not collapse ΔΨ after respiratory inhibition. These findings indicated that ANT was not mediating mitochondrial ATP/ADP exchange in cancer cells [corrected].  We propose that suppression of ANT contributes to low cytosolic ATP/ADP, activation of glycolysis, and a Warburg metabolic phenotype in proliferating cells.
authors.affiliation: From the Center for Cell Death, Injury, and Regeneration, Departments of Drug Discovery and Biomedical Sciences and the Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425 and.
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Maldonado
authors.affiliation: Departments of Drug Discovery and Biomedical Sciences and.
authors.forename: David N
authors.initials: DN
authors.lastname: DeHart
authors.affiliation: Departments of Drug Discovery and Biomedical Sciences and.
authors.forename: Jyoti
authors.identifier: 0000-0003-0755-237X
authors.initials: J
authors.lastname: Patnaik
authors.affiliation: Departments of Drug Discovery and Biomedical Sciences and.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Klatt
authors.affiliation: Departments of Drug Discovery and Biomedical Sciences and.
authors.forename: Monika Beck
authors.initials: MB
authors.lastname: Gooz
authors.affiliation: From the Center for Cell Death, Injury, and Regeneration, Departments of Drug Discovery and Biomedical Sciences and the Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425 and Biochemistry and Molecular Biology, and the Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russian Federation 142290 JJLemasters@musc.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
mesh_terms: D033742:Adenine Nucleotide Translocator 2 / Q000378:metabolism*; D033781:Adenine Nucleotide Translocator 3 / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D033742:Adenine Nucleotide Translocator 2; D033781:Adenine Nucleotide Translocator 3; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate
keywords: ANT; ATP; ATP/ADP turnover; Warburg effect; bongkrekic acid; carboxyatractyloside; glycolysis; mitochondria; voltage-dependent anion channel (VDAC)