Revisiting the Crabtree/Warburg effect in a dynamic perspective: a fitness advantage against sugar-induced cell death

Abstract

The mechanisms behind the Warburg effect in mammalian cells, as well as for the similar Crabtree effect in the yeast Saccharomyces cerevisiae, are still a matter of debate: why do cells shift from the energy-efficient respiration to the energy-inefficient fermentation at high sugar concentration? This review reports on the strong similarities of these phenomena in both cell types, discusses the current ideas, and provides a novel interpretation of their common functional mechanism in a dynamic perspective. This is achieved by analysing another phenomenon, the sugar-induced-cell-death (SICD) occurring in yeast at high sugar concentration, to highlight the link between ATP depletion and cell death. The integration between SICD and the dynamic functioning of the glycolytic process, suggests that the Crabtree/Warburg effect may be interpreted as the avoidance of ATP depletion in those conditions where glucose uptake is higher than the downstream processing capability of the second phase of glycolysis. It follows that the down-regulation of respiration is strategic for cell survival allowing the allocation of more resources to the fermentation pathway, thus maintaining the cell energetic homeostasis.

Keywords: ATP balance; Aerobic glycolysis; cell metabolism.

Figure 1.

Schematic representation of respiration and fermentation pathways and related ATP production in yeast and mammalian cells. Pdc, pyruvate decarboxylase; Pdh, pyruvate dehydrogenase; Aldh, acetaldehyde dehydrogenase; Acs, acetyl-CoA synthetase; Adh, alcohol dehydrogenase; Ldh, lactate dehydrogenase. Adh1 and Adh2, Ldh1 and Ldh2 indicate different isoforms of alcohol dehydrogenase and lactate dehydrogenase, respectively.

Figure 2.

Simplified representation of carbon flux and mitochondrial “bottleneck” at different levels of glucose concentration: (A) respiration; (B) short- and (C) long-term Crabtree/Warburg effects. The key enzymes involved in pyruvate handling are indicated: Pdh (pyruvate dehydrogenase), Pdc (pyruvate decarboxylase) in yeast, and Ldh1 (lactate dehydrogenase) in mammalian cells.

Figure 3.

Ethanol production rate vs. growth rate of several strains of S. cerevisiae in different environmental conditions (Data from [77]).

Figure 4.

S. cerevisiae cell viability under different conditions: cells incubated in pure water (open circles); in water and glucose (closed circles); in water, glucose and phosphate (open triangles). Data from [18] and [21].

Figure 5.

Schematic simplified representation of S. cerevisiae metabolic activity in the different conditions of Fig. 4 (A) water; B) glucose; C) glucose + NaH₂PO₄) and corresponding days of survival until complete loss of viability. Glu, glucose; G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; F1,6BP, fructose 1,6-biphosphate; GA3P, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; Pyr, pyruvate; Eth, ethanol; Ac-CoA, acetyl-coenzyme A; ROS, reactive oxygen species.

Figure 6.

(A) Ethanol production rate vs. sugar uptake rate in different S. cerevisiae cultures (dataset from [77]); (B) Lactate production vs. sugar uptake rate in in vitro preparations of rat small intestine (data from [107]).

Figure 7.

Conceptual representation of glycolysis and associated ATP production balance according to glucose availability. (A) At low glucose uptake rate, the metabolism is fully respiratory, and the ATP balance is positive. (B) Following an increase in glucose availability and consequent higher glucose uptake rate, in the short term, the irreversible reactions of the first phase of glycolysis (GLY I) induce a higher rate of ATP consumption, compared to the ATP production rates during the second phase of glycolysis (GLY II); pyruvate is respired, but its surplus (“overflow”) is fermented. The brown line represents the reduced affinity of the enzyme pyruvate dehydrogenase for high concentrations of pyruvate (“bottleneck”). (C) In the long term at high glucose concentration, the respiration is down-regulated (red dashed line, long term inhibition, LTI) by the accumulation of F1,6BP. Concomitantly, fermentation is increased allowing for a faster conversion of pyruvate which, in turn, increases the flows of the second phase of the glycolysis (GLY II), thus leading to the restoration of a positive balance of ATP production. RESP, respiration; FERM, fermentation; G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; F1,6BP, fructose 1,6-biphosphate; GA3P, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; 1,3BPG, 1,3-bisphosphoglycerate; 3PG, 3-phosphoglycerate; 2PG, 2-phosphoglycerate; PEP, phosphoenolpyruvate; Pyr, pyruvate.