Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming

Abstract

During the process of reprogramming to induced pluripotent stem (iPS) cells, somatic cells switch from oxidative to glycolytic metabolism, a transition associated with profound mitochondrial reorganization. Neither the importance of mitochondrial remodelling for cell reprogramming, nor the molecular mechanisms controlling this process are well understood. Here, we show that an early wave of mitochondrial fragmentation occurs upon expression of reprogramming factors. Reprogramming-induced mitochondrial fission is associated with a minor decrease in mitochondrial mass but not with mitophagy. The pro-fission factor Drp1 is phosphorylated early in reprogramming, and its knockdown and inhibition impairs both mitochondrial fragmentation and generation of iPS cell colonies. Drp1 phosphorylation depends on Erk activation in early reprogramming, which occurs, at least in part, due to downregulation of the MAP kinase phosphatase Dusp6. Taken together, our data indicate that mitochondrial fission controlled by an Erk-Drp1 axis constitutes an early and necessary step in the reprogramming process to pluripotency.

Dysfunctional mitochondrial fission impairs cell reprogramming

“…3A). As we described previously, 28 the expression of the majority of the factors involved in mitochondrial dynamics increased during reprogramming. Interestingly, cells from both genotypes displayed the same profiles of gene ( Fig.…”

“…28,34 Here, we identified MiD51, Mff and Gdap1 as key factors in mediating the remodelling of mitochondria early in reprogramming.…”

“…28 To investigate the factors involved in the regulation of mitochondrial fission during cell reprogramming, we conducted a reprogramming assay where we knocked down factors known to play a major role in controlling mitochondrial fission by RNA interference.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…However, in HeLa cells, prolonged Drp1 downregulation can reduce respiration levels [86], this suggesting that optimal OXPHOS activity requires a balanced equilibrium in mitochondrial morphology. Very recently, even in induced pluripotent stem cells (iPS), the OXPHOS-to-glycolysis switch has been associated with increased mitochondrial fragmentation due to ERK-dependent Drp1 activation [87]. Not only the modulation of mitochondrial morphology can influence respiration and the bioenergetics of the cell, but also the opposite is true.…”

Fission for reprogramming

“…Prieto et al 3 recently reported that the mitochondrial fission protein Drp1 is phosphorylated early in reprogramming by ERK and that Drp1 knockdown and inhibition impair both mitochondrial fragmentation and the generation of iPSC colonies (Fig. 1).…”