title: ATP/ADP ratio, the missed connection between mitochondria and the Warburg effect.
abstract: Non-proliferating cells generate the bulk of cellular ATP by fully oxidizing respiratory substrates in mitochondria. Respiratory substrates cross the mitochondrial outer membrane through only one channel, the voltage dependent anion channel (VDAC). Once in the matrix, respiratory substrates are oxidized in the tricarboxylic acid cycle to generate mostly NADH that is further oxidized in the respiratory chain to generate a proton motive force comprised mainly of membrane potential (ΔΨ) to synthesize ATP. Mitochondrial ΔΨ then drives the release of ATP(4-) from the matrix in exchange for ADP(3-) in the cytosol via the adenine nucleotide translocator (ANT) located in the mitochondrial inner membrane. Thus, mitochondrial function in non-proliferating cells drives a high cytosolic ATP/ADP ratio, essential to inhibit glycolysis. By contrast, the bioenergetics of the Warburg phenotype of proliferating cells is characterized by enhanced aerobic glycolysis and the suppression of mitochondrial metabolism. Suppressed mitochondrial function leads to lower production of mitochondrial ATP and hence lower cytosolic ATP/ADP ratios that favor enhanced glycolysis. Thus, the cytosolic ATP/ADP ratio is a key feature that determines if cell metabolism is predominantly oxidative or glycolytic. Here, we describe two novel mechanisms to explain the suppression of mitochondrial metabolism in cancer cells: the relative closure of VDAC by free tubulin and the inactivation of ANT. Both mechanisms contribute to low ATP/ADP ratios that activate glycolysis.
authors.affiliation: Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC 29425, United States; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Maldonado
authors.affiliation: Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC 29425, United States; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States; Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, United States; Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia. Electronic address: JJLemasters@musc.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology
chemical_list: D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate
keywords: ANT; ATP/ADP ratio; Glycolysis; Oxidative phosphorylation; VDAC; Warburg