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A mitochondrial strategy for safeguarding the reprogrammed genome.

Prigione A, Adjaye J - Cell Regen (Lond) (2014)

Bottom Line: Genomic aberrations induced by somatic cell reprogramming are a major drawback for future applications of this technology in regenerative medicine.A new study by Ji et al. published in Stem Cell Reports suggests a counteracting strategy based on balancing the mitochondrial/oxidative stress pathway through antioxidant supplementation.

View Article: PubMed Central - PubMed

Affiliation: Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Str. 10, D-13125 Berlin-Buch, Germany.

ABSTRACT
Genomic aberrations induced by somatic cell reprogramming are a major drawback for future applications of this technology in regenerative medicine. A new study by Ji et al. published in Stem Cell Reports suggests a counteracting strategy based on balancing the mitochondrial/oxidative stress pathway through antioxidant supplementation.

No MeSH data available.


Related in: MedlinePlus

The induction of pluripotency involves the establishment of a cellular state characterized by low levels of oxidative stress. This is accomplished through a global metabolic restructuring which leads to reduced mitochondrial oxidative phosphorylation (OXPHOS) and increased energy flux towards glycolysis and the pentose phosphate pathway (PPP) (orange arrows). However, this glycolytic shift is not adequately sufficient to prevent the increased leakage of reactive oxygen species (ROS) associated with viral-based four factor (4F) reprogramming. This results in DNA damage that may have detrimental consequences on iPSC functionality (red arrows). The paper by Ji et al. demonstrates that the supplementation with ROS-scavenging molecules provides additional defense against redox imbalance, giving rise to iPSCs bearing fewer genomic aberrations (blue arrows).
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Fig1: The induction of pluripotency involves the establishment of a cellular state characterized by low levels of oxidative stress. This is accomplished through a global metabolic restructuring which leads to reduced mitochondrial oxidative phosphorylation (OXPHOS) and increased energy flux towards glycolysis and the pentose phosphate pathway (PPP) (orange arrows). However, this glycolytic shift is not adequately sufficient to prevent the increased leakage of reactive oxygen species (ROS) associated with viral-based four factor (4F) reprogramming. This results in DNA damage that may have detrimental consequences on iPSC functionality (red arrows). The paper by Ji et al. demonstrates that the supplementation with ROS-scavenging molecules provides additional defense against redox imbalance, giving rise to iPSCs bearing fewer genomic aberrations (blue arrows).

Mentions: Reprogramming somatic cells to pluripotency involves a profound cellular reconfiguration associated with high proliferative rates and a shift towards glycolysis-based metabolism even in the presence of oxygen [8, 9], a situation reminiscent of the Warburg effect that occurs upon cancer transformation. Maintaining the redox equilibrium would therefore be essential for cells undergoing such dramatic restructuring. Indeed, tumor cells re-route the energy flux outside the mitochondria and into the pentose phosphate pathway (PPP) in order to provide important reducing equivalents and diminish the generation of mitochondrial ROS. In this regard, recent evidence suggests that a central player in cancer is pyruvate kinase isoform M2 (PKM2), increased levels of which lead to higher concentrations of glucose-6-phosphate (G6P) and enhanced PPP activity [10]. Interestingly, PKM2 and G6P are also up-regulated upon the induction of pluripotency [11, 12], indicating that similar mechanisms aiming at maintaining redox homeostasis are also in place during reprogramming. Supporting this idea, increased ROS levels promote the differentiation of stem cells [13] and low ROS levels are a characteristic of undifferentiated pluripotent stem cells [8, 14]. However, in agreement with previous observations [4, 5], the work of Ji et al. [3] demonstrates that the redox equilibrium is not sufficiently balanced during reprogramming (FigureĀ 1).Figure 1


A mitochondrial strategy for safeguarding the reprogrammed genome.

Prigione A, Adjaye J - Cell Regen (Lond) (2014)

The induction of pluripotency involves the establishment of a cellular state characterized by low levels of oxidative stress. This is accomplished through a global metabolic restructuring which leads to reduced mitochondrial oxidative phosphorylation (OXPHOS) and increased energy flux towards glycolysis and the pentose phosphate pathway (PPP) (orange arrows). However, this glycolytic shift is not adequately sufficient to prevent the increased leakage of reactive oxygen species (ROS) associated with viral-based four factor (4F) reprogramming. This results in DNA damage that may have detrimental consequences on iPSC functionality (red arrows). The paper by Ji et al. demonstrates that the supplementation with ROS-scavenging molecules provides additional defense against redox imbalance, giving rise to iPSCs bearing fewer genomic aberrations (blue arrows).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230514&req=5

Fig1: The induction of pluripotency involves the establishment of a cellular state characterized by low levels of oxidative stress. This is accomplished through a global metabolic restructuring which leads to reduced mitochondrial oxidative phosphorylation (OXPHOS) and increased energy flux towards glycolysis and the pentose phosphate pathway (PPP) (orange arrows). However, this glycolytic shift is not adequately sufficient to prevent the increased leakage of reactive oxygen species (ROS) associated with viral-based four factor (4F) reprogramming. This results in DNA damage that may have detrimental consequences on iPSC functionality (red arrows). The paper by Ji et al. demonstrates that the supplementation with ROS-scavenging molecules provides additional defense against redox imbalance, giving rise to iPSCs bearing fewer genomic aberrations (blue arrows).
Mentions: Reprogramming somatic cells to pluripotency involves a profound cellular reconfiguration associated with high proliferative rates and a shift towards glycolysis-based metabolism even in the presence of oxygen [8, 9], a situation reminiscent of the Warburg effect that occurs upon cancer transformation. Maintaining the redox equilibrium would therefore be essential for cells undergoing such dramatic restructuring. Indeed, tumor cells re-route the energy flux outside the mitochondria and into the pentose phosphate pathway (PPP) in order to provide important reducing equivalents and diminish the generation of mitochondrial ROS. In this regard, recent evidence suggests that a central player in cancer is pyruvate kinase isoform M2 (PKM2), increased levels of which lead to higher concentrations of glucose-6-phosphate (G6P) and enhanced PPP activity [10]. Interestingly, PKM2 and G6P are also up-regulated upon the induction of pluripotency [11, 12], indicating that similar mechanisms aiming at maintaining redox homeostasis are also in place during reprogramming. Supporting this idea, increased ROS levels promote the differentiation of stem cells [13] and low ROS levels are a characteristic of undifferentiated pluripotent stem cells [8, 14]. However, in agreement with previous observations [4, 5], the work of Ji et al. [3] demonstrates that the redox equilibrium is not sufficiently balanced during reprogramming (FigureĀ 1).Figure 1

Bottom Line: Genomic aberrations induced by somatic cell reprogramming are a major drawback for future applications of this technology in regenerative medicine.A new study by Ji et al. published in Stem Cell Reports suggests a counteracting strategy based on balancing the mitochondrial/oxidative stress pathway through antioxidant supplementation.

View Article: PubMed Central - PubMed

Affiliation: Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Str. 10, D-13125 Berlin-Buch, Germany.

ABSTRACT
Genomic aberrations induced by somatic cell reprogramming are a major drawback for future applications of this technology in regenerative medicine. A new study by Ji et al. published in Stem Cell Reports suggests a counteracting strategy based on balancing the mitochondrial/oxidative stress pathway through antioxidant supplementation.

No MeSH data available.


Related in: MedlinePlus