Prohibitin 2 regulates the proliferation and lineage-specific differentiation of mouse embryonic stem cells in mitochondria.
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.


RESULTS
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
Our results suggest that PHB2 is a crucial mitochondrial regulator for homeostasis and lineage-specific differentiation of ES cells.
Graduate School of Life and Environmental Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan.
Megumi
M
Kowno
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
Kanako
K
Watanabe-Susaki
Graduate School of Life and Environmental Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan; Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
Hisako
H
Ishimine
Department of Anatomy, Saitama Medical School, Moroyama, Iruma, Saitama, Japan.
Shinji
S
Komazaki
Department of Biological Science, Graduate School of Science, The University of Tokyo, Meguro, Tokyo, Japan.
Kei
K
Enomoto
Department of Life Sciences (Biology), Graduate School of Arts and Sciences, The University of Tokyo, Meguro, Tokyo, Japan.
Yasuhiro
Y
Seki
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan; Japan Society for the Promotion of Science (JSPS), Tsukuba, Ibaraki, Japan.
Ying Ying
YY
Wang
Graduate School of Life and Environmental Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan.
Yohei
Y
Ishigaki
Department of Biological Science, Graduate School of Science, The University of Tokyo, Meguro, Tokyo, Japan.
Naoto
N
Ninomiya
Graduate School of Life and Environmental Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan.
Taka-aki K
TA
Noguchi
Graduate School of Life and Environmental Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan.
Yuko
Y
Kokubu
Graduate School of Life and Environmental Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan.
Keigoh
K
Ohnishi
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
Yoshiro
Y
Nakajima
Health Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
Kaoru
K
Kato
Department of Life Sciences (Biology), Graduate School of Arts and Sciences, The University of Tokyo, Meguro, Tokyo, Japan.
Atsushi
A
Intoh
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
Hitomi
H
Takada
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
Norio
N
Yamakawa
Graduate School of Life and Environmental Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan.
Pi-Chao
PC
Wang
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan; Department of Life Sciences (Biology), Graduate School of Arts and Sciences, The University of Tokyo, Meguro, Tokyo, Japan; Life Science Center of Tsukuba Advanced Research Alliance, The University of Tsukuba, Tsukuba, Ibaraki, Japan.
Makoto
M
Asashima
Graduate School of Life and Environmental Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan; Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
Akira
A
Kurisaki
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D019070:Cell Lineage / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D056892:Mediator Complex / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D000091402:Prohibitins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
C539582:Med12 protein, mouse; D056892:Mediator Complex; D024101:Mitochondrial Proteins; C000717333:Phb2 protein, mouse; D000091402:Prohibitins; D012097:Repressor Proteins