The Lkb1 metabolic sensor maintains haematopoietic stem cell survival
- 1 December 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 468 (7324), 659-663
- https://doi.org/10.1038/nature09572
Abstract
Haematopoietic stem cells (HSCs) can convert between growth states that have marked differences in bioenergetic needs. Although often quiescent in adults, these cells become proliferative upon physiological demand. Balancing HSC energetics in response to nutrient availability and growth state is poorly understood, yet essential for the dynamism of the haematopoietic system. Here we show that the Lkb1 tumour suppressor is critical for the maintenance of energy homeostasis in haematopoietic cells. Lkb1 inactivation in adult mice causes loss of HSC quiescence followed by rapid depletion of all haematopoietic subpopulations. Lkb1-deficient bone marrow cells exhibit mitochondrial defects, alterations in lipid and nucleotide metabolism, and depletion of cellular ATP. The haematopoietic effects are largely independent of Lkb1 regulation of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling. Instead, these data define a central role for Lkb1 in restricting HSC entry into cell cycle and in broadly maintaining energy homeostasis in haematopoietic cells through a novel metabolic checkpoint. Haematopoietic stem cells are very sensitive to energetic and oxidative stress, and modulation of the balance between their quiescence and proliferation is needed to respond to metabolic stress while preserving their long-term regenerative capacity. Three new studies show that the tumour suppressor and metabolic sensor Lkb1 has a crucial role in maintaining energy homeostasis in haematopoietic cells. Lkb1 is shown to be necessary for cell-cycle regulation as well as for energy homeostasis, and haematopoietic stem cells depend more acutely on Lkb1 than any other haematopoietic cells. Haematopoietic stem cells (HSCs) are very sensitive to energetic and oxidative stress, and modulation of the balance between their quiescence and proliferation is needed to respond to metabolic stress while preserving HSCs' long term regenerative capacity. Here the tumour suppressor Lkb1 is shown to have a crucial role in maintaining energy homeostasis in haematopoietic cells — an effect largely independent of AMPK and mTOR signalling.Keywords
This publication has 37 references indexed in Scilit:
- The LKB1–AMPK pathway: metabolism and growth control in tumour suppressionNature Reviews Cancer, 2009
- Bmi1 regulates mitochondrial function and the DNA damage response pathwayNature, 2009
- mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilizationProceedings of the National Academy of Sciences of the United States of America, 2008
- Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survivalNature, 2008
- TSC–mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen speciesThe Journal of Experimental Medicine, 2008
- AMP-activated/SNF1 protein kinases: conserved guardians of cellular energyNature Reviews Molecular Cell Biology, 2007
- FoxO Transcription Factors and Stem Cell Homeostasis: Insights from the Hematopoietic SystemCell Stem Cell, 2007
- Regulation of Reactive Oxygen Species by Atm Is Essential for Proper Response to DNA Double-Strand Breaks in LymphocytesThe Journal of Immunology, 2007
- The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stressProceedings of the National Academy of Sciences of the United States of America, 2004
- Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascadeJournal of Biology, 2003