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Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency

Son, M J ; Kwon, Y ; Son, M-Y ; Seol, B ; Choi, H-S ; Ryu, S-W ; Choi, C ; Cho, Y S

Cell death and differentiation, 2015-12, Vol.22 (12), p.1957-1969 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency
Autor: Son, M J ; Kwon, Y ; Son, M-Y ; Seol, B ; Choi, H-S ; Ryu, S-W ; Choi, C ; Cho, Y S
Assuntos: Animals ; Cell Line ; Cellular Reprogramming ; Cyclin-Dependent Kinase Inhibitor p21 - deficiency ; Cyclin-Dependent Kinase Inhibitor p21 - genetics ; GTP Phosphohydrolases - antagonists & inhibitors ; GTP Phosphohydrolases - genetics ; GTP Phosphohydrolases - metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors ; Hypoxia-Inducible Factor 1, alpha Subunit - genetics ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Induced Pluripotent Stem Cells - cytology ; Induced Pluripotent Stem Cells - metabolism ; Mice ; Mice, Knockout ; Mitochondria - metabolism ; Mitochondrial Dynamics ; Mouse Embryonic Stem Cells - cytology ; Mouse Embryonic Stem Cells - metabolism ; Original Paper ; raf Kinases - metabolism ; Reactive Oxygen Species - metabolism ; RNA Interference ; RNA, Small Interfering - metabolism ; Signal Transduction ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tumor Suppressor Protein p53 - deficiency ; Tumor Suppressor Protein p53 - genetics
É parte de: Cell death and differentiation, 2015-12, Vol.22 (12), p.1957-1969
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Descrição: Cell reprogramming technology has allowed the in vitro control of cell fate transition, thus allowing for the generation of highly desired cell types to recapitulate in vivo developmental processes and architectures. However, the precise molecular mechanisms underlying the reprogramming process remain to be defined. Here, we show that depleting p53 and p21, which are barriers to reprogramming, yields a high reprogramming efficiency. Deletion of these factors results in a distinct mitochondrial background with low expression of oxidative phosphorylation subunits and mitochondrial fusion proteins, including mitofusin 1 and 2 (Mfn1/2). Importantly, Mfn1/2 depletion reciprocally inhibits the p53-p21 pathway and promotes both the conversion of somatic cells to a pluripotent state and the maintenance of pluripotency. Mfn1/2 depletion facilitates the glycolytic metabolic transition through the activation of the Ras-Raf and hypoxia-inducible factor 1α (HIF1α) signaling at an early stage of reprogramming. HIF1α is required for increased glycolysis and reprogramming by Mfn1/2 depletion. Taken together, these results demonstrate that Mfn1/2 constitutes a new barrier to reprogramming, and that Mfn1/2 ablation facilitates the induction of pluripotency through the restructuring of mitochondrial dynamics and bioenergetics.
Editor: England: Nature Publishing Group
Idioma: Inglês

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Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency

Son, M J ; Kwon, Y ; Son, M-Y ; Seol, B ; Choi, H-S ; Ryu, S-W ; Choi, C ; Cho, Y S

England: Nature Publishing Group

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