TY - JOUR
T1 - Prohibitin 2 regulates the proliferation and lineage-specific differentiation of mouse embryonic stem cells in mitochondria
AU - Kowno, Megumi
AU - Watanabe-Susaki, Kanako
AU - Ishimine, Hisako
AU - Komazaki, Shinji
AU - Enomoto, Kei
AU - Seki, Yasuhiro
AU - Wang, Ying Ying
AU - Ishigaki, Yohei
AU - Ninomiya, Naoto
AU - Noguchi, Taka Aki K.
AU - Kokubu, Yuko
AU - Ohnishi, Keigoh
AU - Nakajima, Yoshiro
AU - Kato, Kaoru
AU - Intoh, Atsushi
AU - Takada, Hitomi
AU - Yamakawa, Norio
AU - Wang, Pi Chao
AU - Asashima, Makoto
AU - Kurisaki, Akira
N1 - Funding Information:
The expression plasmid for PHB2 was kindly provided by Dr. Endo (Jichi Medical University). The plasmids for PHB2 mutants were given by Dr. Langer (University of Cologne). The knock-in vector pPthC, Cre recombinase expression vector, PCAGGS-Cre, and the mouse ES cell line EBRTcH3 were kind gifts from Drs. Niwa and Masui (RIKEN, Japan). A human iPS cell line, 201B7, was also provided from RIKEN through the National Bio-Resource Project of the MEXT, Japan. The expression vector pCAG-IP was generously given by Dr. Koide (Kanazawa University).
PY - 2014/4/7
Y1 - 2014/4/7
N2 - Background: The pluripotent state of embryonic stem (ES) cells is controlled by a network of specific transcription factors. Recent studies also suggested the significant contribution of mitochondria on the regulation of pluripotent stem cells. However, the molecules involved in these regulations are still unknown. Methodology/Principal Findings: In this study, we found that prohibitin 2 (PHB2), a pleiotrophic factor mainly localized in mitochondria, is a crucial regulatory factor for the homeostasis and differentiation of ES cells. PHB2 was highly expressed in undifferentiated mouse ES cells, and the expression was decreased during the differentiation of ES cells. Knockdown of PHB2 induced significant apoptosis in pluripotent ES cells, whereas enhanced expression of PHB2 contributed to the proliferation of ES cells. However, enhanced expression of PHB2 strongly inhibited ES cell differentiation into neuronal and endodermal cells. Interestingly, only PHB2 with intact mitochondrial targeting signal showed these specific effects on ES cells. Moreover, overexpression of PHB2 enhanced the processing of a dynamin-like GTPase (OPA1) that regulates mitochondrial fusion and cristae remodeling, which could induce partial dysfunction of mitochondria. Conclusions/Significance: Our results suggest that PHB2 is a crucial mitochondrial regulator for homeostasis and lineage-specific differentiation of ES cells.
AB - Background: The pluripotent state of embryonic stem (ES) cells is controlled by a network of specific transcription factors. Recent studies also suggested the significant contribution of mitochondria on the regulation of pluripotent stem cells. However, the molecules involved in these regulations are still unknown. Methodology/Principal Findings: In this study, we found that prohibitin 2 (PHB2), a pleiotrophic factor mainly localized in mitochondria, is a crucial regulatory factor for the homeostasis and differentiation of ES cells. PHB2 was highly expressed in undifferentiated mouse ES cells, and the expression was decreased during the differentiation of ES cells. Knockdown of PHB2 induced significant apoptosis in pluripotent ES cells, whereas enhanced expression of PHB2 contributed to the proliferation of ES cells. However, enhanced expression of PHB2 strongly inhibited ES cell differentiation into neuronal and endodermal cells. Interestingly, only PHB2 with intact mitochondrial targeting signal showed these specific effects on ES cells. Moreover, overexpression of PHB2 enhanced the processing of a dynamin-like GTPase (OPA1) that regulates mitochondrial fusion and cristae remodeling, which could induce partial dysfunction of mitochondria. Conclusions/Significance: Our results suggest that PHB2 is a crucial mitochondrial regulator for homeostasis and lineage-specific differentiation of ES cells.
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U2 - 10.1371/journal.pone.0081552
DO - 10.1371/journal.pone.0081552
M3 - Article
C2 - 24709813
AN - SCOPUS:84899456041
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 4
M1 - e81552
ER -