MDH1-mediated Malate-aspartate NADH Shuttle Maintains the Activity Levels of Fetal Liver Hematopoietic Stem Cells

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2020 May 13

PMID 32396938

Citations 12

Authors

Hao Gu

Chiqi Chen

Xiaoxin Hao

Ni Su

Dan Huang

Yejun Zou

Shu-Hai Lin

Xianjun Chen

Denghao Zheng

Ligen Liu

Zhuo Yu

Li Xie

Yaping Zhang

Xiaoxiao He

Xiaoyun Lai

Xiaocui Zhang

Guo-Qiang Chen

Yuzheng Zhao

Yi Yang

Joseph Loscalzo

Junke Zheng

Affiliations

Soon will be listed here.

Abstract

The connections between energy metabolism and stemness of hematopoietic stem cells (HSCs) at different developmental stages remain largely unknown. We generated a transgenic mouse line for the genetically encoded NADH/NAD+ sensor (SoNar) and demonstrate that there are 3 distinct fetal liver hematopoietic cell populations according to the ratios of SoNar fluorescence. SoNar-low cells had an enhanced level of mitochondrial respiration but a glycolytic level similar to that of SoNar-high cells. Interestingly, 10% of SoNar-low cells were enriched for 65% of total immunophenotypic fetal liver HSCs (FL-HSCs) and contained approximately fivefold more functional HSCs than their SoNar-high counterparts. SoNar was able to monitor sensitively the dynamic changes of energy metabolism in HSCs both in vitro and in vivo. Mechanistically, STAT3 transactivated MDH1 to sustain the malate-aspartate NADH shuttle activity and HSC self-renewal and differentiation. We reveal an unexpected metabolic program of FL-HSCs and provide a powerful genetic tool for metabolic studies of HSCs or other types of stem cells.

Citing Articles

Asparagine Availability Is a Critical Limiting Factor for Infectious Spleen and Kidney Necrosis Virus Replication.

Ma B, Li F, Fu X, Luo X, Lin Q, Liang H Viruses. 2024; 16(10).

PMID: 39459874 PMC: 11512393. DOI: 10.3390/v16101540.

Homeostatic regulation of NAD(H) and NADP(H) in cells.

Chen L, Xing X, Zhang P, Chen L, Pei H Genes Dis. 2024; 11(5):101146.

PMID: 38988322 PMC: 11233901. DOI: 10.1016/j.gendis.2023.101146.

A negative feedback loop underlies the Warburg effect.

Jaiswal A, Singh R NPJ Syst Biol Appl. 2024; 10(1):55.

PMID: 38789545 PMC: 11126737. DOI: 10.1038/s41540-024-00377-x.

Crosstalk between DNA Damage Repair and Metabolic Regulation in Hematopoietic Stem Cells.

Xu J, Fei P, Simon D, Morowitz M, Mehta P, Du W Cells. 2024; 13(9.

PMID: 38727270 PMC: 11083014. DOI: 10.3390/cells13090733.

The acetylation of MDH1 and IDH1 is associated with energy metabolism in acute liver failure.

Shi C, Zhang Y, Chen Q, Wang Y, Zhang D, Guo J iScience. 2024; 27(5):109678.

PMID: 38660411 PMC: 11039345. DOI: 10.1016/j.isci.2024.109678.

References

Yamada K, Hara N, Shibata T, Osago H, Tsuchiya M . The simultaneous measurement of nicotinamide adenine dinucleotide and related compounds by liquid chromatography/electrospray ionization tandem mass spectrometry. Anal Biochem. 2006; 352(2):282-5. DOI: 10.1016/j.ab.2006.02.017. View

Agathocleous M, Meacham C, Burgess R, Piskounova E, Zhao Z, Crane G . Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. 2017; 549(7673):476-481. PMC: 5910063. DOI: 10.1038/nature23876. View

Cabezas-Wallscheid N, Buettner F, Sommerkamp P, Klimmeck D, Ladel L, Thalheimer F . Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy. Cell. 2017; 169(5):807-823.e19. DOI: 10.1016/j.cell.2017.04.018. View

Qian P, He X, Paulson A, Li Z, Tao F, Perry J . The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism. Cell Stem Cell. 2015; 18(2):214-28. PMC: 5545934. DOI: 10.1016/j.stem.2015.11.001. View

Hao X, Gu H, Chen C, Huang D, Zhao Y, Xie L . Metabolic Imaging Reveals a Unique Preference of Symmetric Cell Division and Homing of Leukemia-Initiating Cells in an Endosteal Niche. Cell Metab. 2018; 29(4):950-965.e6. DOI: 10.1016/j.cmet.2018.11.013. View

Chung Y, Park B, Kang Y, Kim T, Eaves C, Oh I . Unique effects of Stat3 on the early phase of hematopoietic stem cell regeneration. Blood. 2006; 108(4):1208-15. DOI: 10.1182/blood-2006-01-010199. View

Abbrescia D, La Piana G, Lofrumento N . Malate-aspartate shuttle and exogenous NADH/cytochrome c electron transport pathway as two independent cytosolic reducing equivalent transfer systems. Arch Biochem Biophys. 2012; 518(2):157-63. DOI: 10.1016/j.abb.2011.12.021. View

Manesia J, Xu Z, Broekaert D, Boon R, van Vliet A, Eelen G . Highly proliferative primitive fetal liver hematopoietic stem cells are fueled by oxidative metabolic pathways. Stem Cell Res. 2015; 15(3):715-721. DOI: 10.1016/j.scr.2015.11.001. View

Darnell Jr J, Kerr I, Stark G . Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994; 264(5164):1415-21. DOI: 10.1126/science.8197455. View

10.

Boisset J, van Cappellen W, Andrieu-Soler C, Galjart N, Dzierzak E, Robin C . In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature. 2010; 464(7285):116-20. DOI: 10.1038/nature08764. View

11.

Takubo K, Nagamatsu G, Kobayashi C, Nakamura-Ishizu A, Kobayashi H, Ikeda E . Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell. 2013; 12(1):49-61. PMC: 6592822. DOI: 10.1016/j.stem.2012.10.011. View

12.

Kocabas F, Zheng J, Thet S, Copeland N, Jenkins N, DeBerardinis R . Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. Blood. 2012; 120(25):4963-72. PMC: 3525021. DOI: 10.1182/blood-2012-05-432260. View

13.

Luchsinger L, Justino de Almeida M, Corrigan D, Mumau M, Snoeck H . Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature. 2016; 529(7587):528-31. PMC: 5106870. DOI: 10.1038/nature16500. View

14.

Yang H, Yang T, Baur J, Perez E, Matsui T, Carmona J . Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell. 2007; 130(6):1095-107. PMC: 3366687. DOI: 10.1016/j.cell.2007.07.035. View

15.

Ido Y . Pyridine nucleotide redox abnormalities in diabetes. Antioxid Redox Signal. 2007; 9(7):931-42. DOI: 10.1089/ars.2007.1630. View

16.

Wang Y, Israelsen W, Lee D, Yu V, Jeanson N, Clish C . Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell. 2014; 158(6):1309-1323. PMC: 4197056. DOI: 10.1016/j.cell.2014.07.048. View

17.

Oh I, Eaves C . Overexpression of a dominant negative form of STAT3 selectively impairs hematopoietic stem cell activity. Oncogene. 2002; 21(31):4778-87. DOI: 10.1038/sj.onc.1205592. View

18.

Gan B, Hu J, Jiang S, Liu Y, Sahin E, Zhuang L . Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature. 2010; 468(7324):701-4. PMC: 3058342. DOI: 10.1038/nature09595. View

19.

Khan J, Mendelson A, Kunisaki Y, Birbrair A, Kou Y, Arnal-Estape A . Fetal liver hematopoietic stem cell niches associate with portal vessels. Science. 2015; 351(6269):176-80. PMC: 4706788. DOI: 10.1126/science.aad0084. View

20.

Yang H, Zhou L, Shi Q, Zhao Y, Lin H, Zhang M . SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth. EMBO J. 2015; 34(8):1110-25. PMC: 4406655. DOI: 10.15252/embj.201591041. View