Mitochondrial activation and the pyruvate paradox in a human cell line.
Pyruvate promotes hyperpolarization of the inner mitochondrial membrane. However, in isolated mitochondria, pyruvate could participate in a futile cycle leading to mitochondrial depolarization. Here, we investigated this paradox in intact human cells by measuring parameters reflecting mitochondrial activation in response to 1 mM pyruvate and 5 mM glucose. NAD(P)H levels were elevated similarly by both substrates. Conversely, pyruvate induced a first transient phase of mitochondrial depolarization before the establishment of the expected sustained hyperpolarization. This correlated with kinetics of cytosolic ATP levels exhibiting a first phase decrease followed by an increase. Therefore, pyruvate transiently depolarizes mitochondria and reduces ATP in intact cells.
de Andrade
Paula B M
PB
Department of Cell Physiology and Metabolism, University Medical Centre, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland.
Casimir
Marina
M
Maechler
Pierre
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D009249:NADP / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012402:Rotenone / Q000494:pharmacology; D013379:Substrate Specificity; D014475:Uncoupling Agents / Q000494:pharmacology
D007476:Ionophores; D024101:Mitochondrial Proteins; D014475:Uncoupling Agents; D012402:Rotenone; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D009249:NADP; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D008156:Luciferases; D005947:Glucose