A Curious Case of Cellular Metabolism

Dear Prof. Emadi,

I read with interest your commentary entitled "A Curious Case of Cellular Metabolism". Unfortunately, I was surprised to see that you failed to acknowledge that most of the reported findings related to mitochondrial modifications within human induced pluripotent stem (iPS) cells (including morphology, activity, and metabolism) were already demonstrated in our paper published last year (Prigione et al, Stem Cells, 2010). For a commentary of our findings, please have a look at this f1000 evaluation: http://f1000biology.com/article/id/2977956/evaluation

If you are interested in this topic, you may be interested to read our recent paper in which we tried to better understand the metabolic reprogramming associated with iPS cell generation (Prigione et al, Stem Cells, 2011). Here, we have used transcriptional data and flux measurements in a similar fashion as Varum and collegues (Varum et al, PLoS One, 2011). In agreement with their data, we found that the protein expression of PDK1 is higher in embryonic stem (ES) cells and iPS cells compared to somatic cells and it consensually decreases upon differentiation of pluripotent stem cells. These findings are also in accordance with the recent demonstration that PDK1 drug inducer PS48 can enhance cellular reprogramming (Zhu et al, Cell Stem Cell, 2010). In addition, we have analyzed the level of key metabolites part of the glycolysis and pentose phosphate pathway (PPP) and detected a significant increase in glucose-6-phosphate (G6P) in both ES and iPS cells compared to somatic cells. G6P is the largest hub of glucose metabolism and its increase may suggest that pluripotent stem cells might divert their energy flux from the glycolytic path into the PPP, which not only provides nucleotide precursors essential for anabolic growth, but also maintains cellular antioxidant defense. Most importantly, we have performed next generation sequencing (NGS) of mitochondrial DNA (mtDNA) to determine whether iPS cells might contain mtDNA mutations not present in the parental cells and whether these mutations could affect the reprogramming of energy metabolism. We unveiled that cellular reprogramming involves a random mtDNA re-arrangement. This process of replicative segregation of mitochondria resembles the mitochondrial genetic bottleneck of embryonic development and suggest the possibility that cellular reprogramming may be used to generate mtDNA mutation-free cells from patients affected by mtDNA disorders. Nonetheless, the reprogramming of energy metabolism appeared maintained in iPS cell lines harboring different mtDNA mutational load, suggesting that the mtDNA alterations may not sufficient to modify the reprogramming- associated modulation of energy metabolism.

The metabolic aspects of stem cells represent a rather under-studied topic. Since reprogramming of energy metabolism is also a hallmark of cancer, we believe that it will be important to determine how the metabolic signature of stem cells differs from the one of tumor cells, in order to design cancer-targeted therapies which will not affect the resident stem cells in the body.

Please do not hesitate to contact me in case you would be interested to discuss these findings in more details.

Sincerely Yours, Alessandro Prigione

-- Alessandro Prigione, MD PhD Molecular Embryology and Aging group Department of Vertebrate Genomics Max-Planck Institute for Molecular Genetics Ihnestrasse 73, D-14195 Berlin, Germany Lab phone: 0049-30-8413-1237 Cell phone: 0049-152-23684564 Fax: 0049-30-8413-1128 E-mail: prigione@molgen.mpg.de