Abstract
O. Warburg conducted one of the first studies on tumor energy metabolism. His early discoveries pointed out that cancer cells display a decreased respiration and an increased glycolysis proportional to the increase in their growth rate, suggesting that they mainly depend on fermentative metabolism for ATP generation. Warburg's results and hypothesis generated controversies that are persistent to this day. It is thus of great importance to understand the mechanisms by which cancer cells can reversibly regulate the two pathways of their energy metabolism as well as the functioning of this metabolism in cell proliferation. Here, we made use of yeast as a model to study the Warburg effect and its eventual function in allowing an increased ATP synthesis to support cell proliferation. The role of oxidative phosphorylation repression in this effect was investigated. We show that yeast is a good model to study the Warburg effect, where all parameters and their modulation in the presence of glucose can be reconstituted. Moreover, we show that in this model, mitochondria are not dysfunctional, but that there are fewer mitochondria respiratory chain units per cell. Identification of the molecular mechanisms involved in this process allowed us to dissociate the parameters involved in the Warburg effect and show that oxidative phosphorylation repression is not mandatory to promote cell growth. Last but not least, we were able to show that neither cellular ATP synthesis flux nor glucose consumption flux controls cellular growth rate.
Highlights
Cell proliferation requires anabolic pathways that require energy for their accomplishment
In order to define whether yeast would be a good model to study the induction of the Warburg effect, these three parameters were assessed in the presence or in the absence of glucose during yeast growth on non-fermentable medium
We investigated the role of this rewiring in promoting cell growth and division
Summary
Cell proliferation requires anabolic pathways that require energy for their accomplishment. A review of the literature shows that the possible benefits of this energy metabolism rewiring for cancer cell growth are not clear It is well-known that aerobic glycolysis is inefficient in terms of ATP synthesis yield when compared with mitochondrial respiration (15–17). Most of the studies conducted in these cells are conducted under hyperglycemic (22.5 mM glucose) and hyperoxic (21% O2) conditions These are two crucial parameters when one considers cell energy metabolism, glucose feeding glycolysis and oxygen being the electrons acceptor in the respiratory chain. From a metabolic point of view, the fermenting yeast Saccharomyces cerevisiae and tumor cells share several features (18, 19) In both cell types, there are mechanisms that enhance glycolytic flux concomitantly with the repression of oxidative phosphorylation in the presence of glucose, and fermentation is preferred even in the presence of oxygen.
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