Regulation Of Cellular Energy Metabolism Research Articles

ATP-regulated K+ channels in cardiac muscle.

An outward current of unknown nature increases significantly when cardiac cells are treated with cyanide or subjected to hypoxia, and decreases on intracellular injection of ATP. We report here that application of the patch-clamp technique to CN-treated mammalian heart cells reveals specific K+ channels which are depressed by intracellular ATP (ATPi) at levels greater than 1 mM. For these channels, conductance in the outward direction is much larger than the inward rectifier K+ channel which is insensitive to ATP. AMP had no effect on the ATP-sensitive K+ channel, and ADP was less effective than ATP. Thus, the ATP-sensitive K+ channel seems to be important for regulation of cellular energy metabolism in the control of membrane excitability.

31P NMR spectroscopy of brain and heart.

31P NMR technique was applied to monitor changes in the energy metabolism of the brain and heart of unanesthetized cats during shock, stroke, hypoxia and increased functional activity. The results show that in these tissues content of inorganic phosphate, sugar phosphates, phosphocreatine and of ATP can be measured decently in awake animals. At the same time this technique has the great advantage over the disruptive biochemical methods that it gives a semi-continuous reading and it is non-invasive. Our findings are summarized as follows: Hemorrhagic shock resulted in an irreversible deterioration of the energy state of the brain. Our stroke model led to a very marked increase in Pi and a decrease CP in the brain but these changes were reversible. The ATP levels of the brain as it was indicated by 31p NMR spectra were not affected by hemorrhagic shock and stroke which can be attributed probably by the reduced rate of ATP consumption. The verification of this hypothesis needs further work. During increased mechanical performance the levels of SP, and Pi increased, ATP decreased, while CP was not influenced in the heart.

Regulation of cellular energy metabolism. The Crabtree effect

The Crabtree effect (inhibition of respiration by glycolysis) is observed in cells with approximately equal glycolytic and respiratory capacities for ATP synthesis. Addition of glucose to aerobic suspensions of glucose-starved cells (Sarcoma 180 ascites tumor cells) causes a burst of respiration and lactate production due to ATP utilization for glucose phosphorylation by hexokinase and phosphofructokinase. This burst of activity is followed by inhibition of both respiration and glycolysis, the former to below the value before glucose addition (Crabtree effect). Both the respiratory rate and the glycolytic flux appear to be regulated by the cytosolic [ ATP] [ ADP][ P i ] albeit by completely different mechanisms. Respiration is regulated by the free energy of hydrolysis of ATP, such that the rate increases as the [ ATP] [ ADP][ P i ] decreases and decreases as the [ ATP] [ ADP][ P i ] increases. The regulatory enzymes of glycolysis are activated by ADP (AMP) and P i and inhibited by ATP. Thus both respiration and glycolysis increase or decrease as the [ ATP] [ ADP][ P i ] decreases or increases. The parallel regulation of both ATP-producing pathways by this common metabolite ratio is consistent with the cytoplasmic [ ATP] [ ADP][ P i ] being an important determinant of homeostatic regulation of cellular energy metabolism.

Homeostatic regulation of cellular energy metabolism: experimental characterization in vivo and fit to a model

Measurements in isolated liver cells, cultured kidney cells, protozoa (Tetrahymena pyriformis), and yeast (Candida utilis) indicate that homeostatic regulation of cellular energy metabolism is of common origin. In every case near equilibrium is maintained between the transfer of reducing equivalents from the intramitochondrial NAD couple to cytochrome c and the phosphorylation of cytosolic ADP to ATP. Under conditions of constant energy demand, changes in the intracellular phosphate concentration cause an adjustment in the [ATP]/[ADP] to maintain a constant [ATP]/[ADP][Pi] and constant respiratory rate. The regulation of mitochondrial respiration occurs as part of the reactions by which reduced cytochrome c is oxidized by molecular oxygen. At similar values for the [ATP]/[ADP][Pi] the respiratory rate increases with increasing reduction of cytochrome c. A model for mitochondrial respiratory control is found to give a good fit to the data in all of the different types of cells tested.