A new study by UCLA stem cell researchers could benefit treatment of cancer and other diseases. The four-year study appears in the November 15 issue of The EMBO Journal, a peer-reviewed journal of the European Molecular Biology Organization. Human pluripotent stem cells are cells that have the potential to develop into any cell type in the body; they rely heavily on glycolysis, or sugar fermentation, to drive their metabolic activities. In contrast, the mature cells to which they give rise depend more on cell mitochondria (microscopic “power plants” contained within cells) to convert sugar and oxygen into carbon dioxide and water during a high energy-producing process called oxidative phosphorylation for their metabolic needs. How cells progress from one form of energy production to another during development is unknown, although a finding by UCLA stem cell researchers provides new insight for this transition that may have implications for using these cells for therapies in the clinic. It had been assumed that pluripotent stem cells contained undeveloped and inactive mitochondria and that these mitochondria could not respire (convert sugar and oxygen into carbon dioxide and water) with the production of energy. This led most scientists to expect that mitochondria matured and gained the ability to respire during the transition from pluripotent stem cells into differentiated body cells over time.
Dr. Michael Teitell, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, collaborated with Carla Koehler, a UCLA professor of chemistry and biochemistry, for the study. Surprisingly, the researchers discovered that pluripotent stem cell mitochondria respire at roughly the same level as differentiated body cells, although they produced very little energy, thereby uncoupling the consumption of sugar and oxygen from energy generation. Rather than finding that mitochondria matured with cell differentiation, as was anticipated, the researchers uncovered a mechanism by which the stem cells converted from glucose fermentation to oxygen-dependent respiration to achieve full differentiation potential. Dr. Teitell noted, “A lot of attention is being paid to the role of metabolism in pluripotent stem cells for making properly differentiated cell lineages for research and potential clinical uses,”
Jin Zhang, a graduate student and first author of the study, discovered that a protein called uncoupling protein 2 (UCP2), was highly expressed in the stem cells. He also found that UCP2 blocked respiration substrates derived from sugar from gaining access to the mitochondria, instead shunting them to the glycolytic and biosynthesis pathways located in the cytoplasm, inhibiting the stem cell’s ability to respire as a method for generating energy. Since metabolism in pluripotent stem cells and cancer cells appear quite similar, Dr, Teitell said the finding could potentially be used to target UCP2 in malignant tumors that express it, of which there are many. Silencing UCP2 could force cancer cells to respire, which might impair their ability to grow quickly.
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