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Cells switch to anaerobic fermentation for rapid growth

17 February 2022
Together with researchers from Delft, Denmark and the United Kingdom, Bas Teusink’s research group from the Systems Biology Lab at VU Amsterdam has found an answer to the question of why cells occasionally switch to anaerobic fermentation when sufficient oxygen is present. The cells appear to make the switch in order to grow faster.

Based on the processes in a yeast cell, the research consortium used a computer model to calculate the best strategy – with or without oxygen – for cells to grow as fast as possible. The researchers mapped every chemical reaction involved in cellular growth, including all the reactions required to build every aspect of the cell’s machinery – its proteins and mitochondria – approximately sixteen thousand reactions in total. The results were recently published in the journal Nature Communications

Muscle cells use oxygen to convert sugars into CO2, water and energy. This is known as respiration: we inhale oxygen, we exhale carbon dioxide and our muscles and brains use the energy released in the process. However, these cells switch to the production of lactic acid when oxygen is in short supply. This process is called fermentation.

Why fermentation?
However, cancer cells (and many rapidly dividing cells such as epithelial cells) switch to lactic acid production even when there is no deficiency of oxygen. This is called the Warburg effect. A similar phenomenon occurs with baker’s yeast used to make beer, wine and bread. If yeast grows slowly, in the presence of oxygen, it burns sugar very efficiently to produce CO2, but if it grows rapidly, yeast switches its strategy and produces alcohol and CO2. The latter process yields much less energy for the cells. Thus, the major fundamental question is: why do these cells switch to fermentation if it provides much less energy?

Benefits and costs
With the aid of a computer model, the researchers calculated which of the two strategies is best for achieving the fastest possible growth. They reached the conclusion that the reason why cells switch to fermentation is closely related to the benefits and costs: respiration may provide more energy, but the machinery required for this, such as the mitochondria in the cells, also consumes a great deal of energy. Fermentation, on the other hand, requires only two enzymes. And rapid growth provides an evolutionary advantage.

Low-cost energy generation
Calculations reveal that when the growth rate is low as a result of low sugar levels, the energy benefits dominate: the cells are forced to operate economically and so the sugar is burned completely. However, as the cells grow more rapidly, the cost of machinery becomes progressively more significant because, in addition to an energy generator, they need a larger number of ‘machines’ to produce the building blocks of the cell at speed. For this reason, cells then switch to a ‘lower-cost’ way of generating energy. 

Better understanding of Warburg effect
The model and the insights can be applied to improve the exploitation of yeast cells for biotechnological applications, such as the production of biofuels or chemicals. Furthermore, the researchers hope that the results will contribute to a better understanding of why the Warburg effect occurs in cancer cells.