title: 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.
authors.affiliation: Departamento de Biología Celular, Universidad de Valencia, Burjassot 46100, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Prieto
authors.affiliation: Departamento de Biología Celular, Universidad de Valencia, Burjassot 46100, Spain.
authors.forename: Marian
authors.initials: M
authors.lastname: León
authors.affiliation: Departamento de Biología Celular, Universidad de Valencia, Burjassot 46100, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Ponsoda
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad de Valencia, Burjassot 46100, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Sendra
authors.affiliation: Unidad de Hepatología Experimental, CIBERehd, Instituto de Investigación Sanitaria La Fe, Valencia 46026, Spain.
authors.forename: Roque
authors.initials: R
authors.lastname: Bort
authors.affiliation: Centre de Medicina Regenerativa de Barcelona, Barcelona 08003, Spain.|Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Madrid 28029, Spain.|Institució Catalana de Recerca i Estudis Avançats, Barcelona 08010, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Ferrer-Lorente
authors.affiliation: Centre de Medicina Regenerativa de Barcelona, Barcelona 08003, Spain.|Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Madrid 28029, Spain.|Institució Catalana de Recerca i Estudis Avançats, Barcelona 08010, Spain.
authors.forename: Angel
authors.identifier: http://orcid.org/0000-0003-2189-9775
authors.initials: A
authors.lastname: Raya
authors.affiliation: Departamento de Biología Celular, Universidad de Valencia, Burjassot 46100, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-García
authors.affiliation: Departamento de Biología Celular, Universidad de Valencia, Burjassot 46100, Spain.
authors.forename: Josema
authors.identifier: http://orcid.org/0000-0001-6906-7164
authors.initials: J
authors.lastname: Torres
mesh_terms: D000818:Animals; D002460:Cell Line; D065150:Cellular Reprogramming; D034281:Dynamins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489428:Myc protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins