The Metabolism of Fast-Growing Cells

All cells require energy to carry out basic functions. For plants, the primary method of energy production is through photosynthesis, while in animal cells, nutrients are broken down to generate highly energetic molecules such as ATP and NADH. One such nutrient is glucose, which is the major source of energy in living organisms. In the cell, glucose is initially broken down to pyruvate through glycolysis, generating some energy in the form of two ATP molecules. From there, the cell can utilize pyruvate through two different pathways to further generate energy: fermentation or respiration. The presence or absence of oxygen has always been thought of as the decision-maker in choosing between these two pathways: if oxygen is available, the cell will undergo aerobic respiration; if no oxygen is available, it would choose anaerobic fermentation instead. The reasoning behind this was simple: respiration, through the citric acid cycle, would produce 36 ATP per pyruvate, while fermentation merely regenerated NAD+, a necessary component of glycolysis, so that pyruvate is not built up and glycolysis can continue.

Overview of respiration and fermentation.
Paradoxically, certain fast-growing cells, including cancer cells, will choose to undergo fermentation instead of respiration even when sufficient oxygen is available. The location of cancer cells can even be visualized by tracking glucose metabolism in the body through PET (positron emission tomography). The process was dubbed the Warburg effect, named after Otto Neinrich Warburg, a German physiologist that studied the metabolism of tumors. Warburg hypothesized that an injury to mitochrondria was a causative driver of tumorigenesis, which was why the initial transition from aerobic respiration to mainly glycolysis occurred. Although debate regarding this hypothesis still exists, Warburg's work on tumor cell metabolism earned him a Nobel Prize in Physiology in 1931.
PET scan of tumors using 18F-FDG (fluorine-18 fluorodeoxyglucose).
There are other cells (such as stem cells) and bacteria that similarly make the decision to use fermentation instead of respiration in the presence of oxygen. In all cases, these are fast-growing cells that would theoretically be better off choosing the more efficient respiration, but undergo fermentation instead. A recent paper in Nature1 discusses a biological reason behind using the less efficient method, and suggests that our calculations of energy production may be a little off.

This is true, except under certain conditions.
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Using E. coli as a model of these fast growing cells, which themselves choose fermentation under aerobic conditions, the group investigated overflow metabolism and proteome efficiency of the two pathways, and how it affected the energetics of the system. Instead of viewing respiration and fermentation on a glucose by glucose basis, they looked at the entire system as a whole, including the energy allocated into producing the proteins involved in either system.

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The proteins involved in glycolysis are required under either pathway, but in respiration, additional proteins are required for both the citric acid cycle and oxidative phosphorylation. When considering energy used to make these proteins (and the ribosomes that make them), it turns out that rapidly dividing cells, which have a primary goal of further cell division (and not much else), will actually find fermentation to be more energetically efficient than respiration. Even though conventional wisdom would tell us that respiration equals more ATP per glucose molecule, after calculating set-up costs, fermentation ends up having a greater net ATP production in these cells. It’s important to note that part of the reason this occurs is due to the carbon-limited nature of these rapidly dividing cells. The cells ration sources of carbon to go towards either the proteome of the cell or towards energy generation, and in the case of rapidly-dividing cells, they would rather divert the few carbons available to makking the less carbon-expensive fermentation proteins than those involved in respiration.

The lead author likened the energy production decision-making process to that of a decision between building a coal power plant or a nuclear power plant2. The fast-growing cells are choosing coal, which would usually be considered the less efficient energy-producing method, since a coal plant would be less expensive to build initially. The analogy can be taken a step further if the decision were occurring in a less wealthy nation, as they will be much less likely to set-up the nuclear plant since they don’t actually have the money to build it.

Choose a side!
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The scientific community is hopeful that these findings in E. coli may apply to other rapidly-dividing cells, like cancer and stem cells. Knowing the way that carbon sources are utilized to make energy in these cells will help us to better model growth in engineered or artificial organisms, and perhaps may even give us additional targets in which to manipulate growth. Let us know what you think the implications of this study are by contacting us at tech@biolegend.com.
References:
  1. Overflow metabolism in E. Coli results from efficient proteome allocation, Nature
  2. The cell's "coal plant": Fermentation, BBC News

Contributed by Ed Chen, PhD.
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