Metabolic switching and cellular dieting

Metabolism may appear to be a very dry subject for those with some basic training in biochemistry. For those who aren't so familiar, metabolism is the study of energy production and expenditure. Cells can produce energy from sugars using two broadly defined pathways; one pathway requires oxygen, and the other doesn't. Scitable has a good introduction that explains the essential components of the two pathways here. For the purposes of this post, I'll restrict my references to these two pathways as glycolysis (no oxygen required) and mitochondria-mediated respiration (requires oxygen). Most eukaryotic cells prefer mitochondria-mediated respiration for energy production mainly because it yields more energy per unit input. So, it's not a huge stretch to think of glycolysis as dieting. Interest in these two pathways has steadily climbed in the past few years because of their apparent importance in cancer development and embryonic development.

Many cell biologists have noted for a long time many similarities between stem cells and cancer cells. Both cell types appear to be in a perverse cellular state that deviates from normal somatic cells. There's emerging evidence that energy production is yet another manifestation of such differences between somatic and cancer/stem cells. In 1924, Otto Warburg and his colleagues¹ first observed that cancer cells used glycolysis (no oxygen required) as the primary mean of energy production even though there was plenty of oxygen around and the mitochondria within those cancer cells were not defective. He mistakenly concluded that cancer is the result of a metabolic disorder. We now know that his observations are the results of genetic mutations that allow cancer cells to switch their metabolic machinery to support stupendous growth in a harsh environment. First, let's imagine how much a single cancer cell must grow in order to form any observable solid tumor. After a few initial cell divisions, the cells begin to form an increasingly dense clump as they continue to divide. The cells at the center of the clump are choked off from oxygen and nutrients because blood vessels don't grow fast enough to supply such rapid growth. Yet, the cells at the center do not die or go into a dormant state, but continue to grow. Where do they find the energy to do that? Warburg's observations proved to be essential for explaining this phenomenon. Since the bulk of the cells are essentially growing in low-oxygen conditions, they must rely on glycolysis rather than mitochondria-mediate respiration to produce energy and sustain growth.

The idea of metabolic switching has gain prominence in recent years because the same type of switch was observed during stem cell development. A paper by Zhou et al.² described stem cells that initially used both glycolysis and mitochondria-mediated respiration for energy, and can switch from one to the other as needed. However, at later stages of development (post-implantation to be exact), the cells switched exclusively to glycolysis. This was actually an unexpected result because it was previously assumed that the mitochondria within stem cells are immature and cannot provide much energy; therefore the stem cells were expected to use glycolysis exclusively. Not only was that untrue (the mitochondria was mature and functional much earlier than expected), but it was the cells at later stages of development that uses glycolysis. It seems eerily similar to tumor formation, if you think about it. As stem cells rapidly divide and differentiate during the earliest stages of development, they also experience temporary suffocation and must rely on glycolysis until blood vessel growth catches up to the expanding tissues. This line of inquiry may inform cancer research if someone figures out how this switch occurs and finds a way to disable it and truly starve a tumor, rather than letting it survive in a dieting state. It may also be useful in stem cell research if metabolism may indeed regulate the very early differentiation and development steps. It could mean more druggable targets and more ways to refine directed differentiation protocols for producing your favorite cell type. I guess metabolism isn't quite so boring, after all.

Image credit: ©ladyada via Flickr (http://www.flickr.com/photos/ladyada/4823921533/)

References

1. O. Warburg, K. Posener, E. Negelein: Ueber den Stoffwechsel der Tumoren. Biochemische Zeitschrift 152, 319-344 (1924). (German). Reprinted in English in the book On metabolism of tumors by O. Warburg, Publisher: Constable, London, 1930.
2. Zhou W, et al. HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition. EMBO J 31, 2103-2116 (2012). doi: 10.1038/emboj.2012.71