Membrane-potential Compensation Reveals Mitochondrial Volume Expansion During HSC Commitment

Overview

Journal Exp Hematol

Specialty Hematology

Date 2018 Nov 6

PMID 30395909

Citations 24

Authors

Massimo Bonora

Kyoko Ito

Claudia Morganti

Paolo Pinton

Keisuke Ito

Affiliations

Soon will be listed here.

Abstract

Proper control of mitochondrial function is a key factor in the maintenance of hematopoietic stem cells (HSCs). Mitochondrial content is commonly measured by staining with fluorescent cationic dyes. However, dye staining can be affected, not only by xenobiotic efflux pumps, but also by dye intake, which is dependent on the negative charge of mitochondria. Therefore, mitochondrial membrane potential (ΔΨ) must be considered in these measurements because a high ΔΨ due to respiratory chain activity can enhance dye intake, leading to the overestimation of mitochondrial volume. Here, we show that HSCs exhibit the highest ΔΨ of the hematopoietic lineages and, as a result, ΔΨ-independent methods most accurately assess the relatively low mitochondrial volumes and DNA amounts of HSC mitochondria. Multipotent progenitor stage or active HSCs display expanded mitochondrial volumes, which decline again with further maturation. Further characterization of the controlled remodeling of the mitochondrial landscape at each hematopoietic stage will contribute to a deeper understanding of the mitochondrial role in HSC homeostasis.

Citing Articles

Hematopoietic stem cell metabolism within the bone marrow niche - insights and opportunities.

Kemna K, van der Burg M, Lankester A, Giera M Bioessays. 2024; 47(2):e2400154.

PMID: 39506498 PMC: 11755706. DOI: 10.1002/bies.202400154.

CXCR4 signaling determines the fate of hematopoietic multipotent progenitors by stimulating mTOR activity and mitochondrial metabolism.

Rondeau V, Kalogeraki M, Roland L, Nader Z, Gourhand V, Bonaud A Sci Signal. 2024; 17(860):eadl5100.

PMID: 39471249 PMC: 11733996. DOI: 10.1126/scisignal.adl5100.

Metabolism and HSC fate: what NADPH is made for.

Morganti C, Bonora M, Ito K Trends Cell Biol. 2024; .

PMID: 39054107 PMC: 11757803. DOI: 10.1016/j.tcb.2024.07.003.

A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.

Bonora M, Morganti C, van Gastel N, Ito K, Calura E, Zanolla I Cell Stem Cell. 2024; 31(3):359-377.e10.

PMID: 38458178 PMC: 10957094. DOI: 10.1016/j.stem.2024.02.004.

Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia.

Zhang Y, Schonberger K, Cabezas-Wallscheid N EMBO J. 2023; 42(24):e112348.

PMID: 38010205 PMC: 10711668. DOI: 10.15252/embj.2022112348.

References

Ho T, Warr M, Adelman E, Lansinger O, Flach J, Verovskaya E . Autophagy maintains the metabolism and function of young and old stem cells. Nature. 2017; 543(7644):205-210. PMC: 5344718. DOI: 10.1038/nature21388. View

Mantel C, OLeary H, Chitteti B, Huang X, Cooper S, Hangoc G . Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell. 2015; 161(7):1553-65. PMC: 4480616. DOI: 10.1016/j.cell.2015.04.054. View

Keij J, Steinkamp J . Staining of mitochondrial membranes with 10-nonyl acridine orange, MitoFluor Green, and MitoTracker Green is affected by mitochondrial membrane potential altering drugs. Cytometry. 2000; 39(3):203-10. DOI: 10.1002/(sici)1097-0320(20000301)39:3<203::aid-cyto5>3.0.co;2-z. View

Goodell M, Rosenzweig M, Kim H, Marks D, Demaria M, Paradis G . Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med. 1997; 3(12):1337-45. DOI: 10.1038/nm1297-1337. View

Sage D, Donati L, Soulez F, Fortun D, Schmit G, Seitz A . DeconvolutionLab2: An open-source software for deconvolution microscopy. Methods. 2017; 115:28-41. DOI: 10.1016/j.ymeth.2016.12.015. View

Simsek T, Kocabas F, Zheng J, DeBerardinis R, Mahmoud A, Olson E . The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell. 2010; 7(3):380-90. PMC: 4159713. DOI: 10.1016/j.stem.2010.07.011. View

Coelho C, Souza A, Derengowski L, de Leon-Rodriguez C, Wang B, Leon-Rivera R . Macrophage mitochondrial and stress response to ingestion of Cryptococcus neoformans. J Immunol. 2015; 194(5):2345-57. PMC: 4340727. DOI: 10.4049/jimmunol.1402350. View

Ito K, Turcotte R, Cui J, Zimmerman S, Pinho S, Mizoguchi T . Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Science. 2016; 354(6316):1156-1160. PMC: 5164878. DOI: 10.1126/science.aaf5530. View

Nicolli A, Basso E, Petronilli V, Wenger R, Bernardi P . Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. J Biol Chem. 1996; 271(4):2185-92. DOI: 10.1074/jbc.271.4.2185. View

10.

Broxmeyer H, OLeary H, Huang X, Mantel C . The importance of hypoxia and extra physiologic oxygen shock/stress for collection and processing of stem and progenitor cells to understand true physiology/pathology of these cells ex vivo. Curr Opin Hematol. 2015; 22(4):273-8. PMC: 4721218. DOI: 10.1097/MOH.0000000000000144. View

11.

Walter D, Lier A, Geiselhart A, Thalheimer F, Huntscha S, Sobotta M . Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature. 2015; 520(7548):549-52. DOI: 10.1038/nature14131. View

12.

Oguro H, Ding L, Morrison S . SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors. Cell Stem Cell. 2013; 13(1):102-16. PMC: 3736853. DOI: 10.1016/j.stem.2013.05.014. View

13.

Shitara H, Shimanuki M, Hayashi J, Yonekawa H . Global imaging of mitochondrial morphology in tissues using transgenic mice expressing mitochondrially targeted enhanced green fluorescent protein. Exp Anim. 2010; 59(1):99-103. DOI: 10.1538/expanim.59.99. View

14.

Kukat C, Larsson N . mtDNA makes a U-turn for the mitochondrial nucleoid. Trends Cell Biol. 2013; 23(9):457-63. DOI: 10.1016/j.tcb.2013.04.009. View

15.

Chandel N, Jasper H, Ho T, Passegue E . Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat Cell Biol. 2016; 18(8):823-32. DOI: 10.1038/ncb3385. View

16.

Scaduto Jr R, Grotyohann L . Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J. 1999; 76(1 Pt 1):469-77. PMC: 1302536. DOI: 10.1016/S0006-3495(99)77214-0. View

17.

Ollion J, Cochennec J, Loll F, Escude C, Boudier T . TANGO: a generic tool for high-throughput 3D image analysis for studying nuclear organization. Bioinformatics. 2013; 29(14):1840-1. PMC: 3702251. DOI: 10.1093/bioinformatics/btt276. View

18.

Zhou S, Schuetz J, Bunting K, Colapietro A, Sampath J, Morris J . The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 2001; 7(9):1028-34. DOI: 10.1038/nm0901-1028. View

19.

Inoue S, Noda S, Kashima K, Nakada K, Hayashi J, Miyoshi H . Mitochondrial respiration defects modulate differentiation but not proliferation of hematopoietic stem and progenitor cells. FEBS Lett. 2010; 584(15):3402-9. DOI: 10.1016/j.febslet.2010.06.036. View

20.

Ito K, Ito K . Hematopoietic stem cell fate through metabolic control. Exp Hematol. 2018; 64:1-11. PMC: 6084457. DOI: 10.1016/j.exphem.2018.05.005. View