The mitochondrial respiratory chain is essential for haematopoietic stem cell function

Nature Cell Biology

Volumn 19, Issue 6, 2017, Pages 614-625

  Ansó, Elena ^a   Weinberg, Samuel E ^a   Diebold, Lauren P ^a   Thompson, Benjamin J ^a   Malinge, Sébastien ^a   Schumacker, Paul T ^a   Liu, Xin ^b   Zhang, Yuannyu ^b,c   Shao, Zhen ^c   Steadman, Mya ^d   Marsh, Kelly M ^d   Xu, Jian ^b   Crispino, John D ^a   Chandel, Navdeep S ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c Chinese Academy of Sciences   (China)

^d AGIOS PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 HYDROXYGLUTARIC ACID; IRON SULFUR PROTEIN; NICOTINAMIDE ADENINE DINUCLEOTIDE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE; UBIQUINOL CYTOCHROME C REDUCTASE; ALPHA-HYDROXYGLUTARATE; GLUTARIC ACID DERIVATIVE; RIESKE IRON-SULFUR PROTEIN;

ADULT; ANEMIA; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL DIFFERENTIATION; CELL FUNCTION; CELL LINEAGE; CELL MATURATION; CELL POPULATION; CELL PROLIFERATION; CONTROLLED STUDY; DNA METHYLATION; EPIGENETICS; FEMALE; FETUS; FETUS DEATH; GENE EXPRESSION; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; HISTONE METHYLATION; MITOCHONDRIAL RESPIRATION; MOUSE; NONHUMAN; OXYGEN CONSUMPTION; PANCYTOPENIA; PRIORITY JOURNAL; PROTEIN DEFICIENCY; PROTEIN DEPLETION; PROTEIN FUNCTION; STEM CELL; ADULT STEM CELL; ANIMAL; BLOOD; C57BL MOUSE; CELL AGING; CELL CULTURE; CELL DEATH; COMPARATIVE STUDY; DEFICIENCY; ELECTRON TRANSPORT; ENERGY METABOLISM; FETAL STEM CELL; GENETIC EPIGENESIS; GENETICS; GENOTYPE; KNOCKOUT MOUSE; METABOLISM; MITOCHONDRION; PATHOLOGY; PHENOTYPE; PREGNANCY; SIGNAL TRANSDUCTION; TIME FACTOR;

ADULT STEM CELLS; ANEMIA; ANIMALS; CELL AGING; CELL DEATH; CELL PROLIFERATION; CELLS, CULTURED; ELECTRON TRANSPORT; ELECTRON TRANSPORT COMPLEX III; ENERGY METABOLISM; EPIGENESIS, GENETIC; FEMALE; FETAL STEM CELLS; GENOTYPE; GLUTARATES; HEMATOPOIESIS; HEMATOPOIETIC STEM CELLS; MICE, INBRED C57BL; MICE, KNOCKOUT; MITOCHONDRIA; NAD; PHENOTYPE; PREGNANCY; SIGNAL TRANSDUCTION; TIME FACTORS;

EID: 85020255453     PISSN: 14657392     EISSN: 14764679     Source Type: Journal    
DOI: 10.1038/ncb3529     Document Type: Article

References (57)

1. Chandel, N. S., Jasper, H., Ho, T. T. & Passegue, E. Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat. Cell Biol. 18, 823-832 (2016).
2. Ito, K. & Suda, T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat. Rev. Mol. Cell Biol. 15, 243-256 (2014).
3. Takubo, K. et al. Regulation of glycolysis by pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12, 49-61 (2013).
4. Adelman, D. M., Maltepe, E. & Simon, M. C. Multilineage embryonic hematopoiesis requires hypoxic ARNT activity. Genes Dev. 13, 2478-2483 (1999).
5. Simsek, T. et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7, 380-390 (2010).
6. Norddahl, G. L. et al. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell 8, 499-510 (2011).
7. Parmar, K., Mauch, P., Vergilio, J.-A., Sackstein, R. & Down, J. D. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc. Natl Acad. Sci. USA 104, 5431-5436 (2007).
8. Spencer, J. A. et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508, 269-273 (2014).
9. Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325-339 (2007).
10. Ito, K. et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat. Med. 12, 446-451 (2006).
11. Chen, C. et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J. Experim. Med. 205, 2397-2408 (2008).
12. Jung, H. et al. TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress. Cell Metab. 18, 75-85 (2013).
13. Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997-1002 (2004).
14. Maryanovich, M. et al. The ATM-BID pathway regulates quiescence and survival of haematopoietic stem cells. Nat. Cell Biol. 14, 535-541 (2012).
15. Ahlqvist, K. J. et al. Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab. 15, 100-109 (2012).
16. Maryanovich, M. et al. An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate. Nat. Commun. 6, 7901 (2015).
17. Yu, W.-M. et al. Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell Stem Cell 12, 62-74 (2013).
18. Gan, B. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701-704 (2010).
19. Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659-663 (2010).
20. Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653-658 (2010).
21. Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225-236 (2013).
22. Ema, H. & Nakauchi, H. Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood 95, 2284-2288 (2000).
23. Larsson, N. G. et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat. Genet. 18, 231-236 (1998).
24. Martinez-Reyes, I. et al. TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol. Cell 61, 199-209 (2016).
25. Orkin, S. H. & Zon, L. I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631-644 (2008).
26. McDonnell, E. et al. Lipids reprogram metabolism to become a major carbon source for histone acetylation. Cell Rep. 17, 1463-1472 (2016).
27. Losman, J. A. & Kaelin, W. G. Jr What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836-852 (2013).
28. Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of -ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17-30 (2011).
29. Xiao, M. et al. Inhibition of -KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326-1338 (2012).
30. Sullivan, L. B. et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51, 236-248 (2013).
31. Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-tomesenchymal transition. Nature 537, 544-547 (2016).
32. Engqvist, M. K., Esser, C., Maier, A., Lercher, M. J. & Maurino, V. G. Mitochondrial 2-hydroxyglutarate metabolism. Mitochondrion 19B, 275-281 (2014).
33. Oldham, W. M., Clish, C. B., Yang, Y. & Loscalzo, J. Hypoxia-mediated increases in l-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 22, 291-303 (2015).
34. Chowdhury, R. et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463-469 (2011).
35. Birsoy, K. et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162, 540-551 (2015).
36. Sullivan, L. B. et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162, 552-563 (2015).
37. Chandel, N. S. Evolution of mitochondria as signaling organelles. Cell Metab. 22, 204-206 (2015).
38. Tormos, K. V. et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab. 14, 537-544 (2011).
39. Hamanaka, R. B. et al. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci. Signal. 6, ra8 (2013).
40. Owusu-Ansah, E. & Banerjee, U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461, 537-541 (2009).
41. Zhang, J. et al. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J. 30, 4860-4873 (2011).
42. Mullen, A. R. et al. Oxidation of -ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep. 7, 1679-1690 (2014).
43. Shim, E. H. et al. L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 4, 1290-1298 (2014).
44. Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788-8793 (2010).
45. Wheaton, W. W. et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 3, e02242 (2014).
46. Evans, D. R. & Guy, H. I. Mammalian pyrimidine biosynthesis: fresh insights into an ancient pathway. J. Biol. Chem. 279, 33035-33038 (2004).
47. Mullen, A. R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385-388 (2012).
48. Liu, X. et al. Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation. Nat. Cell Biol. http://dx.doi.org/10.1038/ncb3527 (2017).
49. Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225-236 (2013).
50. Trapnell, C., Pachter, L. & Salzberg, S. L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105-1111 (2009).
51. Anders, S., Pyl, P. T. & Huber, W. HTSeq-a Python framework to work with highthroughput sequencing data. Bioinformatics 31, 166-169 (2015).
52. Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511-515 (2010).
53. Lu, W. et al. Metabolomic analysis via reversed-phase ion-pairing liquid chromatography coupled to a stand alone orbitrap mass spectrometer. Anal. Chem. 82, 3212-3221 (2010).
54. Garcia, B. A. et al. Chemical derivatization of histones for facilitated analysis by mass spectrometry. Nat. Protoc. 2, 933-938 (2007).
55. Zheng, Y., Tipton, J. D., Thomas, P. M., Kelleher, N. L. & Sweet, S. M. Site-specific human histone H3 methylation stability: fast K4me3 turnover. Proteomics 14, 2190-2199 (2014).
56. Zheng, Y., Thomas, P. M. & Kelleher, N. L. Measurement of acetylation turnover at distinct lysines in human histones identifies long-lived acetylation sites. Nat. Commun. 4, 2203 (2013).
57. MacLean, B. et al. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 26, 966-968 (2010).