Abstract
Chemicals inducing a mild decrease in the ATP/ADP ratio are considered as caloric restriction mimetics as well as treatments against obesity. Screening for such chemicals in animal model systems requires a lot of time and labor. Here, we present a system for the rapid screening of non-toxic substances causing such a de-energization of cells. We looked for chemicals allowing the growth of yeast lacking trehalose phosphate synthase on a non-fermentable carbon source in the presence of glucose. Under such conditions, the cells cannot grow because the cellular phosphate is mostly being used to phosphorylate the sugars in upper glycolysis, while the biosynthesis of bisphosphoglycerate is blocked. We reasoned that by decreasing the ATP/ADP ratio, one might prevent the phosphorylation of the sugars and also boost bisphosphoglycerate synthesis by providing the substrate, i.e., inorganic phosphate. We confirmed that a complete inhibition of oxidative phosphorylation alleviates the block. As our system includes a non-fermentable carbon source, only the chemicals that did not cause a complete block of mitochondrial ATP synthesis allowed the initial depletion of glucose followed by respiratory growth. Using this system, we found two novel compounds, dodecylmethyl diphenylamine (FS1) and diethyl (tetradecyl) phenyl ammonium bromide (Kor105), which possess a mild membrane-depolarizing activity.
Highlights
A mild decrease in the ATP/ADP ratio can be beneficial for cells [1]
Since the mutant cells cannot be kept on solid YP-glycerol medium, we used YP-ethanol media
As we have shown earlier [18], the cycle of uncoupling includes the passage of a pair uncoupler-free fatty acid (FFA) across the membrane (Figure 5B)
Summary
A mild decrease in the ATP/ADP ratio can be beneficial for cells [1] Such a decrease could be achieved by various means, i.e., by adding chemicals dissipating mitochondrial membrane potential [1,2], moderating the mitochondrial respiratory machinery [3] or decreasing the rate of glycolysis (reviewed in [4]). Such chemicals are promising drugs for treating obesity; they can be considered as caloric restriction mimetics. TPS1 is a gene coding for trehalose phosphate synthase, a protein acting to remove excessive intracellular
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