Reference

naturensp 420Nat. Commun. 7:11124 doi: 10.1038/ncomms11124 (2016).

Authors

Javier Prieto, Marian León, Xavier Ponsoda, Ramón Sendra, Roque Bort, Raquel Ferrer-Lorente, Angel Raya, Carlos López-García y Josema Torres.

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.

Description

La reprogramación celular es un proceso dinámico en el cual las células somáticas deben superar diversas barreras celulares y moleculares antes de alcanzar el estadio final de pluripotencia inducida. En este trabajo mostramos que la reorganización mitocondrial es una de las primeras barreras que las células deben salvar para alcanzar dicho estado. Esta reorganización tiene lugar gracias a una profunda fisión mitocondrial mediada por la proteína DRP1. Hemos demostrado que durante los primeros días de la reprogramación se produce un silenciamiento de la fosfatasa DUSP6, lo que favorece la fosforilación de DRP1 a través de una activación transitoria de ERK1/2. DRP1 fosforilada se recluta hacia la mitocondria para orquestar el proceso de fisión mitocondrial.

 

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REFERENCIA DEL GRUPO INVESTIGADOR

El grupo del Dr. Josema Torres se enmarca dentro de la Unidad de Neurobiología Celular de la Universidad de Valencia. Su investigación se centra en los mecanismos celulares y moleculares que gobiernan la pluripotencia celular, así como su adquisición o pérdida durante la reprogramación y diferenciación celular, respectivamente. En el campo de la medicina traslacional el grupo utiliza las células pluripotentes inducidas para desarrollar modelos humanos y murinos que ayuden al estudio y tratamiento de enfermedades neurodegenerativas como Charcot-Marie-Tooth o Parkinson.

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