Somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by forced expression of Oct4 (also known as Pouf5.1), Sox2, Klf4 and c-Myc. Reprogramming of somatic cells is a stepwise process and cells must overcome several barriers before reaching the pluripotent state.
Mitochondria are key organelles for cellular homeostasis that join by fusion and divide by fission. Fusion is mediated by Mitofusin-1 and -2 (Mfn1 and Mfn2) and optic atrophy 1 (Opa1) proteins located at the outer and inner mitochondrial membranes, respectively. Fission is mediated by dynamin-related protein 1 (Drp1), a cytosolic protein that, on activation, is recruited to the surface of mitochondria with the collaboration of accessory proteins, such mitochondrial fission factor (Mff), mitochondrial fission protein 1 (Fis1) or mitochondrial elongation factor 1 and 2 (Mief1/MiD51 and Mief2/MiD49, respectively). Mitochondrial fission starts by the formation of an initial constriction in the mitochondria at contact sites with the endoplasmic reticulum. Activated Drp1 is then recruited to the constricted mitochondrial membrane, forming a ring that eventually fragments mitochondria in a GTPase-dependent manner.
Recently, it was shown that phosphorylation of DRP1-S616 by ERK2 promotes mitochondrial fission and mitogen-activated protein kinase (MAPK)-driven tumor growth. Although recent reports have highlighted the importance of mitochondria in cell reprogramming from a metabolic perspective, the role of the dynamics of these organelles in this process remains unexplored.
Researchers 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.
Mitochondrial fission necessary for cell reprogramming
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