Open AccessA Critical Role of Mitochondrial Phosphatase Ptpmt1 in Embryogenesis Reveals a Mitochondrial Metabolic Stress-Induced Differentiation Checkpoint in Embryonic Stem Cells
Author(s) -
Jinhua Shen,
Xia Liu,
Wen Mei Yu,
Jie Liu,
Milou Groot Nibbelink,
Caiying Guo,
Toren Finkel,
Cheng Kui Qu
Publication year - 2011
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.05629-11
Subject(s) - biology , microbiology and biotechnology , embryonic stem cell , cellular differentiation , stem cell , mitochondrion , biochemistry , gene
Mitochondria are highly dynamic organelles that play multiple roles in cells. How mitochondria cooperatively modulate embryonic stem (ES) cell function during development is not fully understood. Global disruption ofPtpmt1 , a mitochondrial Pten-like phosphatidylinositol phosphate (PIP) phosphatase, resulted in developmental arrest and postimplantation lethality.Ptpmt1 −/− blastocysts failed to outgrow, and inner-cell-mass cells failed to thrive. Depletion ofPtpmt1 in conditional knockout ES cells decreased proliferation without affecting energy homeostasis or cell survival. Differentiation ofPtpmt1 -depleted ES cells was essentially blocked. This was accompanied by upregulation of cyclin-dependent kinase inhibitors and a significant cell cycle delay. Reintroduction of wild-type but not of catalytically deficient Ptpmt1 C132S or truncated Ptpmt1 lacking the mitochondrial localization signal restored the differentiation capabilities ofPtpmt1 knockout ES cells. Intriguingly, Ptpmt1 is specifically important for stem cells, as ablation ofPtpmt1 in differentiated embryonic fibroblasts did not disturb cellular function. Further analyses demonstrated that oxygen consumption ofPtpmt1 -depleted cells was decreased, while glycolysis was concomitantly enhanced. In addition, mitochondrial fusion/dynamics were compromised inPtpmt1 knockout cells due to accumulation of PIPs. These studies, while establishing a crucial role for Ptpmt1 phosphatase in embryogenesis, reveal a mitochondrial metabolic stress-activated checkpoint in the control of ES cell differentiation.