Mitochondrial control of hematopoietic stem cell balance and hematopoiesis

Abstract

Hematopoietic stem cells (HSCs) are stem cells from mesodermal derivation that reside in bone marrow and provide blood cells for the whole life of an adult individual, through a process called hematopoiesis. The long lasting support of HSCs for hematopoiesis is permitted by the fine regulation of quiescence and division output. Exit from the quiescent state is to produce a committed and/or stem daughter cells, in an event defined asymmetric or symmetric division. A deregulation in the proportion between asymmetric and symmetric divisions is critical in the appearance of hematological disorders ranging from bone marrow failure to hematological malignancies. Over the past years, several studies have indicated how the metabolism of HSCs is determinant in the regulation of HSC quiescence and commitment process. A metabolism shifted to the glycolytic pathway promotes HSCs quiescence and sustainment of hematopoiesis. Boosting mitochondrial respiration promotes the stem cell commitment followed by stem pool exhaustion, and minimal mitochondrial activity is required to maintain the HSCs quiescence. In the present review are discussed the most recent advances in comprehension of the roles of mitochondria in the hematopoiesis and in the division balance.

Keywords

mitochondria / metabolism / hematopoiesis / hematopoietic stem cells / division balance / hypoxia inducible factor 1 alpha (Hif-1α)

References

[1] Arruda A P, Pers B M, Parlakgül G, Güney E, Inouye K, Hotamisligil G S (2014). Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat Med, 20(12): 1427–1435

[2] Beckmann J, Scheitza S, Wernet P, Fischer J C, Giebel B (2007). Asymmetric cell division within the human hematopoietic stem and progenitor cell compartment: identification of asymmetrically segregating proteins. Blood, 109(12): 5494–5501

[3] Bononi A, Bonora M, Marchi S, Missiroli S, Poletti F, Giorgi C, Pandolfi P P, Pinton P (2013). Identification of PTEN at the ER and MAMs and its regulation of Ca(2+) signaling and apoptosis in a protein phosphatase-dependent manner. Cell Death Differ, 20(12): 1631–1643

[4] Bononi A, Missiroli S, Poletti F, Suski J M, Agnoletto C, Bonora M, De Marchi E, Giorgi C, Marchi S, Patergnani S, Rimessi A, Wieckowski M R, Pinton P (2012). Mitochondria-associated membranes (MAMs) as hotspot Ca(2+) signaling units. Adv Exp Med Biol, 740: 411–437

[5] Bonora M, De Marchi E, Patergnani S, Suski J M, Celsi F, Bononi A, Giorgi C, Marchi S, Rimessi A, Duszyński J, Pozzan T, Wieckowski M R, Pinton P (2014). Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process. Cell Death Differ, 21(8): 1198–1208

[6] Bonora M, Patergnani S, Rimessi A, De Marchi E, Suski J M, Bononi A, Giorgi C, Marchi S, Missiroli S, Poletti F, Wieckowski M R, Pinton P (2012). ATP synthesis and storage. Purinergic Signal, 8(3): 343–357

[7] Bonora M, Pinton P (2014). The mitochondrial permeability transition pore and cancer: molecular mechanisms involved in cell death. Front Oncol, 4: 302

[8] Carracedo A, Cantley L C, Pandolfi P P (2013). Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer, 13(4): 227–232

[9] Chen C, Liu Y, Liu R, Ikenoue T, Guan K L, Liu Y, Zheng P (2008). TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med, 205(10): 2397–2408

[10] Dalton C M, Carroll J (2013). Biased inheritance of mitochondria during asymmetric cell division in the mouse oocyte. J Cell Sci, 126(Pt 13): 2955–2964

[11] Galluzzi L, Pietrocola F, Levine B, Kroemer G (2014). Metabolic control of autophagy. Cell, 159(6): 1263–1276

[12] Gan B, Hu J, Jiang S, Liu Y, Sahin E, Zhuang L, Fletcher-Sananikone E, Colla S, Wang Y A, Chin L, Depinho R A (2010). Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature, 468(7324): 701–704

[13] Giebel B, Zhang T, Beckmann J, Spanholtz J, Wernet P, Ho A D, Punzel M (2006). Primitive human hematopoietic cells give rise to differentially specified daughter cells upon their initial cell division. Blood, 107(5): 2146–2152

[14] Giorgi C, Bonora M, Missiroli S, Poletti F, Ramirez F G, Morciano G, Morganti C, Pandolfi P P, Mammano F, Pinton P (2014). Intravital imaging reveals p53-dependent cancer cell death induced by phototherapy via calcium signaling. Oncotarget, 6(3): 1435–1445

[15] Giorgi C, Bonora M, Sorrentino G, Missiroli S, Poletti F, Suski J M, Ramirez G, Rizzuto R, Di Virgilio F, Zito E, Pandolfi P P, Wieckowski M R, Mammano F, Del Sal G, Pinton P (2015). p53 at the endoplasmic reticulum regulates apoptosis in a Ca²⁺-dependent manner. Proc Natl Acad Sci, 112(6): 1779–1784

[16] Green D R, Galluzzi L, Kroemer G (2014). Cell biology. Metabolic control of cell death. Science, 345(6203): 1250256

[17] Gurumurthy S, Xie S Z, Alagesan B, Kim J, Yusuf R Z, Saez B, Tzatsos A, Ozsolak F, Milos P, Ferrari F, Park P J, Shirihai O S, Scadden D T, Bardeesy N (2010). The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature, 468(7324): 659–663

[18] Higuchi R, Vevea J D, Swayne T C, Chojnowski R, Hill V, Boldogh I R, Pon L A (2013). Actin dynamics affect mitochondrial quality control and aging in budding yeast. Curr Biol, 23(23): 2417–2422

[19] Inoue S, Noda S, Kashima K, Nakada K, Hayashi J, Miyoshi H (2010). Mitochondrial respiration defects modulate differentiation but not proliferation of hematopoietic stem and progenitor cells. FEBS Lett, 584(15): 3402–3409

[20] Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan D E, Teruya-Feldstein J, Pandolfi P P (2008). PML targeting eradicates quiescent leukaemia-initiating cells. Nature, 453(7198): 1072–1078

[21] Ito K, Carracedo A, Weiss D, Arai F, Ala U, Avigan D E, Schafer Z T, Evans R M, Suda T, Lee C H, Pandolfi P P (2012). A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med, 18(9): 1350–1358

[22] Ito K, Suda T (2014). Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol, 15(4): 243–256

[23] Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S, Zhang D, Mizoguchi T, Wei Q, Lucas D, Ito K, Mar J C, Bergman A, Frenette P S (2013). Arteriolar niches maintain haematopoietic stem cell quiescence. Nature, 502(7473): 637–643

[24] Leary A G, Strauss L C, Civin C I, Ogawa M (1985). Disparate differentiation in hemopoietic colonies derived from human paired progenitors. Blood, 66(2): 327–332

[25] Liu F, Lee J Y, Wei H, Tanabe O, Engel J D, Morrison S J, Guan J L (2010). FIP200 is required for the cell-autonomous maintenance of fetal hematopoietic stem cells. Blood, 116(23): 4806–4814

[26] Mantel C, Messina-Graham S, Broxmeyer H E (2010). Upregulation of nascent mitochondrial biogenesis in mouse hematopoietic stem cells parallels upregulation of CD34 and loss of pluripotency: a potential strategy for reducing oxidative risk in stem cells. Cell Cycle, 9(10): 2008–2017

[27] Marchi S, Patergnani S, Pinton P (2014). The endoplasmic reticulum-mitochondria connection: one touch, multiple functions. Biochim Biophys Acta, 1837(4): 461–469

[28] McKenzie J L, Takenaka K, Gan O I, Doedens M, Dick J E (2007). Low rhodamine 123 retention identifies long-term human hematopoietic stem cells within the Lin^-CD34⁺CD38^- population. Blood, 109(2): 543–545

[29] Mendelson A, Frenette P S (2014). Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med, 20(8): 833–846

[30] Morrison S J, Kimble J (2006). Asymmetric and symmetric stem-cell divisions in development and cancer. Nature, 441(7097): 1068–1074

[31] Mortensen M, Ferguson D J, Edelmann M, Kessler B, Morten K J, Komatsu M, Simon A K (2010). Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo. Proc Natl Acad Sci USA, 107(2): 832–837

[32] Nakada D, Saunders T L, Morrison S J (2010). Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature, 468(7324): 653–658

[33] Pagliarini D J, Wiley S E, Kimple M E, Dixon J R, Kelly P, Worby C A, Casey P J, Dixon J E (2005). Involvement of a mitochondrial phosphatase in the regulation of ATP production and insulin secretion in pancreatic beta cells. Mol Cell, 19(2): 197–207

[34] Patergnani S, Pinton P (2015). Mitophagy and mitochondrial balance. Methods Mol Biol, 1241: 181–194

[35] Piccoli C, Ria R, Scrima R, Cela O, D’Aprile A, Boffoli D, Falzetti F, Tabilio A, Capitanio N (2005). Characterization of mitochondrial and extra-mitochondrial oxygen consuming reactions in human hematopoietic stem cells. Novel evidence of the occurrence of NAD(P)H oxidase activity. J Biol Chem, 280(28): 26467–26476

[36] Ploemacher R E, Brons N H (1988a). In vivo proliferative and differential properties of murine bone marrow cells separated on the basis of rhodamine-123 retention. Exp Hematol, 16(11): 903–907

[37] Ploemacher R E, Brons N H (1988b). Isolation of hemopoietic stem cell subsets from murine bone marrow: II. Evidence for an early precursor of day-12 CFU-S and cells associated with radioprotective ability. Exp Hematol, 16(1): 27–32

[38] Prowse A B, Chong F, Elliott D A, Elefanty A G, Stanley E G, Gray P P, Munro T P, Osborne G W (2012). Analysis of mitochondrial function and localisation during human embryonic stem cell differentiation in vitro. PLoS ONE, 7(12): e52214

[39] Rehman J (2010). Empowering self-renewal and differentiation: the role of mitochondria in stem cells. J Mol Med (Berl), 88(10): 981–986

[40] Rimessi A, Bonora M, Marchi S, Patergnani S, Marobbio C M, Lasorsa F M, Pinton P (2013). Perturbed mitochondrial Ca²⁺ signals as causes or consequences of mitophagy induction. Autophagy, 9(11): 1677–1686

[41] Romero-Moya D, Bueno C, Montes R, Navarro-Montero O, Iborra F J, López L C, Martin M, Menendez P (2013). Cord blood-derived CD34⁺ hematopoietic cells with low mitochondrial mass are enriched in hematopoietic repopulating stem cell function. Haematologica, 98(7): 1022–1029

[42] Schroeder T (2007). Asymmetric cell division in normal and malignant hematopoietic precursor cells. Cell Stem Cell, 1(5): 479–481

[43] Simsek T, Kocabas F, Zheng J, Deberardinis R J, Mahmoud A I, Olson E N, Schneider J W, Zhang C C, Sadek H A (2010). The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell, 7(3): 380–390

[44] Spencer J A, Ferraro F, Roussakis E, Klein A, Wu J, Runnels J M, Zaher W, Mortensen L J, Alt C, Turcotte R, Yusuf R, Côté D, Vinogradov S A, Scadden D T, Lin C P (2014). Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature, 508(7495): 269–273

[45] Staiber W (2007). Asymmetric distribution of mitochondria and of spindle microtubules in opposite directions in differential mitosis of germ line cells in Acricotopus. Cell Tissue Res, 329(1): 197–203

[46] Suda T, Suda J, Ogawa M (1984). Disparate differentiation in mouse hemopoietic colonies derived from paired progenitors. Proc Natl Acad Sci USA, 81(8): 2520–2524 (Research Support, U.S. Gov’t, Non-P.H.S. Research Support, U.S. Gov’t, P.H.S.)

[47] Takahashi S, Tanaka T, Sakai J (2007). New therapeutic target for metabolic syndrome: PPARdelta. Endocr J, 54(3): 347–357

[48] Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson R S, Hirao A, Suematsu M, Suda T (2010). Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell, 7(3): 391–402

[49] Takubo K, Nagamatsu G, Kobayashi C I, Nakamura-Ishizu A, Kobayashi H, Ikeda E, Goda N, Rahimi Y, Johnson R S, Soga T, Hirao A, Suematsu M, Suda T (2013). Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell, 12(1): 49–61

[50] Ting S B, Deneault E, Hope K, Cellot S, Chagraoui J, Mayotte N, Dorn J F, Laverdure J P, Harvey M, Hawkins E D, Russell S M, Maddox P S, Iscove N N, Sauvageau G (2012). Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2. Blood, 119(11): 2510–2522

[51] Vance J E (2014). MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond. Biochim Biophys Acta, 1841(4): 595–609

[52] Vega-Naredo I, Loureiro R, Mesquita K A, Barbosa I A, Tavares L C, Branco A F, Erickson J R, Holy J, Perkins E L, Carvalho R A, Oliveira P J (2014). Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells. Cell Death Differ, 21(10): 1560–1574

[53] Wallace D C, Chalkia D (2013). Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb Perspect Biol, 5(11): a021220

[54] Wanet A, Remacle N, Najar M, Sokal E, Arnould T, Najimi M, Renard P (2014). Mitochondrial remodeling in hepatic differentiation and dedifferentiation. Int J Biochem Cell Biol, 54: 174–185

[55] Wang Y H, Israelsen W J, Lee D, Yu V W, Jeanson N T, Clish C B, Cantley L C, Vander Heiden M G, Scadden D T (2014). Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell, 158(6): 1309–1323

[56] Weissman I L, Anderson D J, Gage F (2001). Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu Rev Cell Dev Biol, 17(1): 387–403

[57] Wu M, Kwon H Y, Rattis F, Blum J, Zhao C, Ashkenazi R, Jackson T L, Gaiano N, Oliver T, Reya T (2007). Imaging hematopoietic precursor division in real time. Cell Stem Cell, 1(5): 541–554

[58] Yu W M, Liu X, Shen J, Jovanovic O, Pohl E E, Gerson S L, Finkel T, Broxmeyer H E, Qu C K (2013). Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell Stem Cell, 12(1): 62–74

[59] Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller K I, Dang C V, Semenza G L (2007). HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell, 11(5): 407–420

[60] Zhang Y, Marsboom G, Toth P T, Rehman J (2013). Mitochondrial respiration regulates adipogenic differentiation of human mesenchymal stem cells. PLoS ONE, 8(10): e77077

[61] Zimdahl B, Ito T, Blevins A, Bajaj J, Konuma T, Weeks J, Koechlein C S, Kwon H Y, Arami O, Rizzieri D, Broome H E, Chuah C, Oehler V G, Sasik R, Hardiman G, Reya T (2014). Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia. Nat Genet, 46(3): 245–252

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