ATP/ADP Turnover and Import of Glycolytic ATP into Mitochondria in Cancer Cells Is Independent of the Adenine Nucleotide Translocator

作者：Maldonado Eduardo N; DeHart David N; Patnaik Jyoti; Klatt Sandra C; Gooz Monika Beck; Lemasters John J^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291(37): 19642-19650.

DOI：10.1074/jbc.M116.734814

• ATP
• glycolysis
• mitochondria
• voltage-dependent anion channel (VDAC)
• Warburg effect
• ANT
• ATP
• ADP turnover
• bongkrekic acid
• carboxyatractyloside

Non-proliferating cells oxidize respiratory substrates in mitochondria to generate a protonmotive force (p) that drives ATP synthesis. The mitochondrial membrane potential (), a component of p, 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 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 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 after respiratory inhibition. These findings indicated that ANT did mediate mitochondrial ATP/ADP exchange in cancer cells. We propose that suppression of ANT contributes to low cytosolic ATP/ADP, activation of glycolysis, and a Warburg metabolic phenotype in proliferating cells.

• 出版日期2016-9-9