Transient Activation of Mitoflashes Modulates Nanog at the Early Phase of Somatic Cell Reprogramming

• Mitoflashes increase transiently at the early phase of reprogramming
• Mitoflash activation at the early phase enhances reprogramming
• Mitoflash activation enhances reprogramming through upregulating Nanog expression
• Mitoflash activation decreases Nanog promoter’s methylation status by Tet2 occupancy

SummaryThe mechanisms of somatic cell reprogramming have been revealed at multiple levels. However, the lack of tools to monitor different reactive oxygen species (ROS) has left their distinct signals and roles in reprogramming unknown. We hypothesized that mitochondrial flashes (mitoflashes), recently identified spontaneous bursts of mitochondrial superoxide signaling, play a role in reprogramming. Here we show that the frequency of mitoflashes transiently increases, accompanied by flash amplitude reduction, during the early stages of reprogramming. This transient activation of mitoflashes at the early stage enhances reprogramming, whereas sustained activation impairs reprogramming. The reprogramming-promoting function of mitoflashes occurs via the upregulation of Nanog expression that is associated with decreases in the methylation status of the Nanog promoter through Tet2 occupancy. Together our findings provide a previously unknown role for superoxide signaling mediated epigenetic regulation in cell fate determination.

Graphical AbstractFigure optionsDownload high-quality image (97 K)Download as PowerPoint slide