BPS2026 – Bcl-xL expression induces a Warburg-like metabolic shift in yeast cultivated under glucose respiro-fermentative conditions

It is now well-established that shifts in energy metabolism are associated with cancer development and progression. The most studied of these phenomena is the Warburg effect, which corresponds to an increase in anaerobic glycolysis vs. mitochondrial oxidative phosphorylation. Bcl-2 family proteins contain both pro- (e.g., Bax), and anti-apoptotic (e.g., Bcl-2 and Bcl-xL) members. Up-regulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL have been commonly associated with blood cancers; and certain studies indicate that Bcl-2 family proteins might play a role in the regulation of energy metabolism. However, the study of the molecular mechanisms involved in Bcl-2/xL regulation of carbohydrate metabolism is challenging as mammalian cell models contain several Bcl-2/xL gene homologs encoding proteins with possible redundant functions. The yeast S. cerevisiae is a eukaryotic cell model which possesses the advantages of (1) not possessing any Bcl-2 family gene homologs and (2) having been used to study the regulatory role of Bcl-2 family proteins during mitochondrial apoptosis for decades. A 13 C-NMR-based detection and quantification of extracellular glucose-derived metabolites allowed us to observe that Bcl-xL expression was associated with a significant increase of alcoholic fermentation of yeast cultivated in respiro-fermentative conditions (i.e., 0.5% w/v). This Bcl-xL-mediated effect was also shown to happen concurrently with a decrease in the growth yield. On the contrary, yeast expressing Bcl-2 showed unaltered alcoholic fermentation and growth yield in the same conditions. These results suggest that Bcl-xL (but not Bcl-2) expression plays an active role in the stimulation of fermentation and the triggering of a Warburg type effect commonly observed during cancer.