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

Autores de IIS La Fe

• Javier Prieto Martinez

  Autor

• Montserrat León Fabregas

  Autor

• Xavier Ponsoda Marti

  Autor

• Ramon Sendra Perez

  Autor

• Bernardo Roque Bort Martí

  Autor

• Carlos Lopez Garcia

  Autor

• Jose Manuel Torres Ibañez

  Autor

Participantes ajenos a IIS La Fe

• Ferrer-Lorente R
• Raya A

Grupos

• Hepatología experimental y Trasplante hepático

• Neumología

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.