Mitochondrial Heterogeneity in Stem Cells

  • Prajna Paramita Naik
  • Prakash P. Praharaj
  • Chandra S. Bhol
  • Debasna P. Panigrahi
  • Kewal K. Mahapatra
  • Srimanta Patra
  • Sarbari Saha
  • Sujit K. BhutiaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1123)


Mitochondria are customarily acknowledged as the powerhouse of the cell by virtue of their indispensable role in cellular energy production. In addition, it plays an important role in pluripotency, differentiation, and reprogramming. This review describes variation in the stem cells and their mitochondrial heterogeneity. The mitochondrial variation can be described in terms of structure, function, and subcellular distribution. The mitochondria cristae development status and their localization patterns determine the oxygen consumption rate and ATP production which is a central controller of stem cell maintenance and differentiation. Generally, stem cells show spherical, immature mitochondria with perinuclear distribution. Such mitochondria are metabolically less energetic and low polarized. Moreover, mostly glycolytic energy production is found in pluripotent stem cells with a variation in naïve stem cells which perform oxidative phosphorylation (OXPHOS). This article also describes the structural and functional journey of mitochondria during development. Future insight into underlying mechanisms associated with such alternation in mitochondria of stem cells during embryonic stages could uncover mitochondrial adaptability on cellular demands. Moreover, investigating the importance of mitochondria in pluripotency maintenance might unravel the cause of mitochondrial diseases, aging, and regenerative therapies.


Mitochondria Stem cells Mitochondrial heterogeneity Embryonic development 


  1. 1.
    Naik PP, Birbrair A, Bhutia SK (2019) Mitophagy-driven metabolic switch reprograms stem cell fate. Cell Mol Life Sci 76:27–43PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Raff M (2003) Adult stem cell plasticity: fact or artifact? Annu Rev Cell Dev Biol 19:1–22PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Lonergan T, Bavister B, Brenner C (2007) Mitochondria in stem cells. Mitochondrion 7:289–296PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Nichols J, Smith A (2009) Naive and primed pluripotent states. Cell Stem Cell 4:487–492PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Wallace DC, Singh G, Lott MT et al (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242:1427–1430PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Anderson S, Bankier AT, Barrell BG et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158–167PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125:1241–1252PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Xu X, Duan S, Yi F, Ocampo A, Liu G-H, Belmonte JCI (2013) Mitochondrial regulation in pluripotent stem cells. Cell Metab 18:325–332PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Karbowski M, Youle R (2003) Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ 10(8):870PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Brandt J, Martin A, Lucas F, Vorbeck M (1974) The structure of rat liver mitochondria: a reevaluation. Biochem Biophys Res Commun 59:1097–1103PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Hoffmann H-P, Avers CJ (1973) Mitochondrion of yeast: ultrastructural evidence for one giant, branched organelle per cell. Science 181:749–751PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Rizzuto R, Brini M, Murgia M, Pozzan T (1993) Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science 262:744–747PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Collins TJ, Berridge MJ, Lipp P, Bootman MD (2002) Mitochondria are morphologically and functionally heterogeneous within cells. EMBO J 21:1616–1627PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    De Giorgi F, Lartigue L, Ichas F (2000) Electrical coupling and plasticity of the mitochondrial network. Cell Calcium 28:365–370PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Amchenkova AA, Bakeeva LE, Chentsov YS, Skulachev VP, Zorov DB (1988) Coupling membranes as energy-transmitting cables. I. Filamentous mitochondria in fibroblasts and mitochondrial clusters in cardiomyocytes. J Cell Biol 107(2):481–495PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Chen H, Chan DC (2009) Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases. Hum Mol Genet 18(R2):R169–R176PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Simon J, Bhatnagar PL, Milburn NS (1969) An electron microscope study of changes in mitochondria of flight muscle of ageing houseflies (Musca domestica). J Insect Physiol 15:135–140PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Yaffe MP (1999) The machinery of mitochondrial inheritance and behavior. Science 283:1493–1497PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Johnson PR, Dolman NJ, Pope M et al (2003) Non-uniform distribution of mitochondria in pancreatic acinar cells. Cell Tissue Res 313(1):37–45PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Bruce JI, Giovannucci DR, Blinder G, Shuttleworth TJ, Yule DI (2004) Modulation of [Ca2+] i signaling dynamics and metabolism by perinuclear mitochondria in mouse parotid acinar cells. J Biol Chem 279(13):12,909–12,917CrossRefGoogle Scholar
  23. 23.
    Park MK, Ashby MC, Erdemli G, Petersen OH, Tepikin AV (2001) Perinuclear, perigranular and sub-plasmalemmal mitochondria have distinct functions in the regulation of cellular calcium transport. EMBO J 20(8):1863–1874PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Ord M (1979) The effects of chemicals and radiations within the cell: an ultrastructural and micrurgical study using Amoeba proteusas a single-cell model. Int Rev Cytol 61:229–281PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Jahangir A, Holmuhamedov E, Terzic A (1999) Two mitochondrial populations in the heart: Are subsarcolemmal mitochondria the primary target of mitochondrial K-ATP channel opener action? Lippincott Williams & Wilkins, Philadelphia, PA, p 343Google Scholar
  26. 26.
    Battersby BJ, Moyes CD (1998) Are there distinct subcellular populations of mitochondria in rainbow trout red muscle? J Exp Biol 201:2455–2460PubMedPubMedCentralGoogle Scholar
  27. 27.
    Van Blerkom J (2009) Mitochondria in early mammalian development. Semin Cell Dev Biol 20:354–364PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Mitchell P, Moyle J (1967) Chemiosmotic hypothesis of oxidative phosphorylation. Nature 213:137PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Van Blerkom J (2004) Mitochondria in human oogenesis and preimplantation embryogenesis: engines of metabolism, ionic regulation and developmental competence. Reproduction 128:269–280PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Facucho-Oliveira JM, Alderson J, Spikings EC, Egginton S, John JCS (2007) Mitochondrial DNA replication during differentiation of murine embryonic stem cells. J Cell Sci 120:4025–4034PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Prigione A, Ruiz-Pérez MV, Bukowiecki R, Adjaye J (2015) Metabolic restructuring and cell fate conversion. Cell Mol Life Sci 72:1759–1777PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Bukowiecki R, Adjaye J, Prigione A (2014) Mitochondrial function in pluripotent stem cells and cellular reprogramming. Gerontology 60:174–182PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Zhang J, Khvorostov I, Hong JS et al (2011) UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J 30:4860–4873PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Varum S, Rodrigues AS, Moura MB et al (2011) Energy metabolism in human pluripotent stem cells and their differentiated counterparts. PLoS One 6:e20914PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Motta PM, Nottola SA, Makabe S, Heyn R (2000) Mitochondrial morphology in human fetal and adult female germ cells. Hum Reprod 15(Suppl 2):129–147PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    St. John JC, Ramalho-Santos J, Gray HL et al (2005) The expression of mitochondrial DNA transcription factors during early cardiomyocyte in vitro differentiation from human embryonic stem cells. Cloning Stem Cells 7:141–153PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Todd LR, Damin MN, Gomathinayagam R, Horn SR, Means AR, Sankar U (2010) Growth factor erv1-like modulates Drp1 to preserve mitochondrial dynamics and function in mouse embryonic stem cells. Mol Biol Cell 21:1225–1236PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Squirrell J, Schramm R, Paprocki A, Wokosin DL, Bavister BD (2003) Imaging mitochondrial organization in living primate oocytes and embryos using multiphoton microscopy. Microsc Microanal 9:190–201PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Batten BE, Albertini DF, Ducibella T (1987) Patterns of organelle distribution in mouse embryos during preimplantation development. Am J Anat 178:204–213PubMedCrossRefGoogle Scholar
  40. 40.
    Wilding M, Dale B, Marino M et al (2001) Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos. Hum Reprod 16:909–917PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Naik PP, Panda PK, Bhutia SK (2017) Oral cancer stem cells microenvironment. Adv Exp Med Biol 1041:207–233PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Naik PP, Das DN, Panda PK et al (2016) Implications of cancer stem cells in developing therapeutic resistance in oral cancer. Oral Oncol 62:122–135PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Naik PP, Mukhopadhyay S, Panda PK et al (2018) Autophagy regulates cisplatin-induced stemness and chemoresistance via the upregulation of CD 44, ABCB 1 and ADAM 17 in oral squamous cell carcinoma. Cell Prolif 51:e12411CrossRefGoogle Scholar
  44. 44.
    Zhou W, Choi M, Margineantu D et al (2012) HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition. EMBO J 31:2103–2116PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Teslaa T, Teitell MA (2014) Pluripotent stem cell energy metabolism: an update. EMBO J 34:138–153PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Yanes O, Clark J, Wong DM et al (2010) Metabolic oxidation regulates embryonic stem cell differentiation. Nat Chem Biol 6:411PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Chen CT, Shih YRV, Kuo TK, Lee OK, Wei YH (2008) Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells 26:960–968PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Ito K, Suda T (2014) Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 15:243–256PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Simsek T, Kocabas F, Zheng J et al (2010) The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7:380–390PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Pattappa G, Thorpe SD, Jegard NC, Heywood HK, de Bruijn JD, Lee DA (2012) Continuous and uninterrupted oxygen tension influences the colony formation and oxidative metabolism of human mesenchymal stem cells. Tissue Eng Part C Methods 19:68–79PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Geißler S, Textor M, Kühnisch J et al (2012) Functional comparison of chronological and in vitro aging: differential role of the cytoskeleton and mitochondria in mesenchymal stromal cells. PLoS One 7:e52700PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Birket MJ, Orr AL, Gerencser AA et al (2011) A reduction in ATP demand and mitochondrial activity with neural differentiation of human embryonic stem cells. J Cell Sci 124:348–358PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Candelario KM, Shuttleworth CW, Cunningham LA (2013) Neural stem/progenitor cells display a low requirement for oxidative metabolism independent of hypoxia inducible factor-1alpha expression. J Neurochem 125:420–429PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Gershon TR, Crowther AJ, Tikunov A et al (2013) Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma. Cancer Metab 1:2PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Solá S, Morgado AL, Rodrigues CM (2013) Death receptors and mitochondria: two prime triggers of neural apoptosis and differentiation. Biochim Biophys Acta 1830:2160–2166PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Stern S, Biggers JD, Anderson E (1971) Mitochondria and early development of the mouse. J Exp Zool 176:179–191PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Barnett DK, Kimura J, Bavister BD (1996) Translocation of active mitochondria during hamster preimplantation embryo development studied by confocal laser scanning microscopy. Dev Dyn 205:64–72PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Van Blerkom J (1991) Microtubule mediation of cytoplasmic and nuclear maturation during the early stages of resumed meiosis in cultured mouse oocytes. Proc Natl Acad Sci 88:5031–5035PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Bavister BD, Squirrell JM (2000) Mitochondrial distribution and function in oocytes and early embryos. Hum Reprod 15(Suppl 2):189–198PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Van Blerkom J, Davis P, Alexander S (2000) Differential mitochondrial distribution in human pronuclear embryos leads to disproportionate inheritance between blastomeres: relationship to microtubular organization, ATP content and competence. Hum Reprod 15:2621–2633PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Lonergan T, Brenner C, Bavister B (2006) Differentiation-related changes in mitochondrial properties as indicators of stem cell competence. J Cell Physiol 208:149–115PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Houghton FD (2006) Energy metabolism of the inner cell mass and trophectoderm of the mouse blastocyst. Differentiation 74:11–18PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Brinster RL (1967) Protein content of the mouse embryo during the first five days of development. J Reprod Fertil 13:413–420PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Leese HJ (2012) Metabolism of the preimplantation embryo: 40 years on. Reproduction 143:417–427PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Martin KL, Leese HJ (1995) Role of glucose in mouse preimplantation embryo development. Mol Reprod Dev 40:436–443PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Jansen S, Pantaleon M, Kaye PL (2008) Characterization and regulation of monocarboxylate cotransporters Slc16a7 and Slc16a3 in preimplantation mouse embryos. Biol Reprod 79:84–92PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Pantaleon M, Kaye PL (1998) Glucose transporters in preimplantation development. Rev Reprod 3:77–81PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Shyh-Chang N, Daley GQ, Cantley LC (2013) Stem cell metabolism in tissue development and aging. Development 140:2535–2547PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Praefcke GJ, McMahon HT (2004) The dynamin superfamily: universal membrane tubulation and fission molecules? Nat Rev Mol Cell Biol 5:133–147PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Hermann GJ, Thatcher JW, Mills JP et al (1998) Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p. J Cell Biol 143:359–373PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Bleazard W, McCaffery JM, King EJ et al (1999) The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat Cell Biol 1:298–304PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Labrousse AM, Zappaterra MD, Rube DA, van der Bliek AM (1999) C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol Cell 4:815–826PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Sesaki H, Jensen RE (1999) Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J Cell Biol 147:699–706PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Okamoto K, Shaw JM (2005) Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu Rev Genet 39:503–536PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Verstreken P, Ly CV, Venken KJ, Koh TW, Zhou Y, Bellen HJ (2005) Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47:365–378PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Song M, Mihara K, Chen Y, Scorrano L, Dorn GW (2015) Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab 21:273–285PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Mattenberger Y, James DI, Martinou J-C (2003) Fusion of mitochondria in mammalian cells is dependent on the mitochondrial inner membrane potential and independent of microtubules or actin. FEBS Lett 538:53–59PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Twig G, Elorza A, Molina AJ et al (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Mao K, Klionsky DJ (2013) Mitochondrial fission facilitates mitophagy in Saccharomyces cerevisiae. Autophagy 9:1900–1901PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Frank M, Duvezin-Caubet S, Koob S et al (2012) Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim Biophys Acta 1823:2297–2310PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Son MY, Choi H, Han YM, Sook Cho Y (2013) Unveiling the critical role of REX1 in the regulation of human stem cell pluripotency. Stem Cells 31:2374–2387PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Prieto J, León M, Ponsoda X et al (2016) Dysfunctional mitochondrial fission impairs cell reprogramming. Cell Cycle 15:3240–3250PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Son M, Kwon Y, Son M et al (2015) Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency. Cell Death Differ 22:1957–1969PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Vazquez-Martin A, Cufí S, Corominas-Faja B, Oliveras-Ferraros C, Vellon L, Menendez JA (2012) Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: new insight into the role of mitophagy in cell stemness. Aging 4:393PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Prajna Paramita Naik
    • 1
    • 2
  • Prakash P. Praharaj
    • 1
  • Chandra S. Bhol
    • 1
  • Debasna P. Panigrahi
    • 1
  • Kewal K. Mahapatra
    • 1
  • Srimanta Patra
    • 1
  • Sarbari Saha
    • 1
  • Sujit K. Bhutia
    • 1
    Email author
  1. 1.Department of Life ScienceNational Institute of Technology RourkelaRourkelaIndia
  2. 2.P.G. Department of ZoologyVikram Deb (Auto) CollegeJeyporeIndia

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