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Biogerontology

, Volume 15, Issue 1, pp 1–12 | Cite as

The systems biology of mitochondrial fission and fusion and implications for disease and aging

  • Anuradha Chauhan
  • Julio Vera
  • Olaf Wolkenhauer
Review Article

Abstract

Mitochondria organize themselves as dynamic populations within a cell, by undergoing continuous cycles of fission and fusion. The spatio-temporal distribution and abundance of mitochondria determines the cell’s energy budget and is thus intimately linked to the cell’s response to environmental stimuli during aging. The dynamic balance of mitochondrial fission and fusion can be studied in terms of antagonistic subpopulations that regulate the mitochondrial responses in space and time. The dynamic nature of these processes motivates mathematical modelling and the simulation of such complex process. In several neurodegenerative and metabolic diseases the dynamic balance of fission and fusion is disturbed. However, how this dynamics plays a role in the progression of diseases is largely unclear. Fission and fusion help mitochondria to regulate cellular energy (ATP) levels, and minimize accumulation of harmful oxidized material called reactive oxygen species which accelerate mutations in mitochondrial DNA (mtDNA) during aging. We discuss how systems biology approaches can be used to investigate the mechanisms controlling the fission–fusion dynamics under two categories: dissecting the design of its molecular regulatory motifs, and understanding complex mitochondrial responses through their population level interactions. This will help us to understand how different regulatory mechanisms regulate the ATP and mutation (mtDNA) landscape of mitochondria to a variety of environmental stimuli in order to maintain their function during aging.

Keywords

Mitochondria Fission Fusion Aging Antagonistic interactions Adaptation 

Notes

Acknowledgements

We are thankful to our ROSage collaborators, in particular, Markus Tiedge and Simone Baltrusch for valuable interactions. Also, we are grateful to Andrew Ferree and Orian Shirihai for the valuable discussion and their comments on the earlier versions of the paper. This work was supported by the German Federal Ministry of Education and Research (BMBF) as part of the project ROSAge [0315892A to AC, JV, OW].

References

  1. Alon U (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8(6):450–461PubMedCrossRefGoogle Scholar
  2. Aon MA, Cortassa S, O’Rourke B (2006) The fundamental organization of cardiac mitochondria as a network of coupled oscillators. Biophys J 91(11):4317–4327PubMedCentralPubMedCrossRefGoogle Scholar
  3. Aon MA, Cortassa S, O’Rourke B (2008) Mitochondrial oscillations in physiology and pathophysiology. Adv Exp Med Biol 641:98–117PubMedCentralPubMedCrossRefGoogle Scholar
  4. Area-Gomez E, Del Carmen Lara Castillo M, Tambini MD, Guardia-Laguarta C, de Groof AJC, Madra M, Ikenouchi J, Umeda M, Bird TD, Sturley SL, Schon EA (2012) Upregulated function of mitochondria-associated er membranes in alzheimer disease. EMBO J 31(21):4106–4123PubMedCrossRefGoogle Scholar
  5. Arnheim N, Cortopassi G (1992) Deleterious mitochondrial dna mutations accumulate in aging human tissues. Mutat Res 275(3-6):157–167PubMedCrossRefGoogle Scholar
  6. Balźsi G, van Oudenaarden A, Collins JJ (2011) Cellular decision making and biological noise: from microbes to mammals. Cell 144(6):910–925CrossRefGoogle Scholar
  7. Bandy B, Davison AJ (1990) Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Radic Biol Med 8(6):523–539PubMedCrossRefGoogle Scholar
  8. Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006) High levels of mitochondrial dna deletions in substantia nigra neurons in aging and parkinson disease. Nat Genet 38(5):515–517PubMedCrossRefGoogle Scholar
  9. Berman SB, Pineda FJ, Hardwick JM (2008) Mitochondrial fission and fusion dynamics: the long and short of it. Cell Death Differ 15(7):1147–1152PubMedCentralPubMedCrossRefGoogle Scholar
  10. Blackstone C, Chang CR (2011) Mitochondria unite to survive. Nat Cell Biol 13(5):521–522PubMedCrossRefGoogle Scholar
  11. Bogenhagen DF (2010) Does mtdna nucleoid organization impact aging. Exp Gerontol 45(7-8):473–477PubMedCentralPubMedCrossRefGoogle Scholar
  12. Bossy-Wetzel E, Barsoum MJ, Godzik A, Schwarzenbacher R, Lipton SA (2003) Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr Opin Cell Biol 15(6):706–716PubMedCrossRefGoogle Scholar
  13. Cartoni R, Lger B, Hock MB, Praz M, Crettenand A, Pich S, Ziltener JL, Luthi F, Driaz O, Zorzano A, Gobelet C, Kralli A, Russell AP (2005) Mitofusins 1/2 and erralpha expression are increased in human skeletal muscle after physical exercise. J Physiol 567(Pt 1):349–358Google Scholar
  14. Cereghetti GM, Stangherlin A, Martinsde Brito O, Chang CR, Blackstone C, Bernardi P, Scorrano L (2008) Dephosphorylation by calcineurin regulates translocation of drp1 to mitochondria. Proc Natl Acad Sci USA 105(41):15,803–15,808CrossRefGoogle Scholar
  15. Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125(7):1241–1252PubMedCrossRefGoogle Scholar
  16. Chang CR, Blackstone C (2010) Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein drp1. Ann N Y Acad Sci 1201:34–39PubMedCrossRefGoogle Scholar
  17. Chauhan A, Lorenzen S, Herzel H, Bernard S (2011) Regulation of mammalian cell cycle progression in the regenerating liver. J Theor Biol 283(1):103–112PubMedCrossRefGoogle Scholar
  18. Chen H, Chomyn A, Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280(28):26,185–26,192CrossRefGoogle Scholar
  19. Collins TJ, Berridge MJ, Lipp P, Bootman MD (2002) Mitochondria are morphologically and functionally heterogeneous within cells. EMBO J 21(7):1616–1627PubMedCrossRefGoogle Scholar
  20. Comet JP, Noual M, Richard A, Aracena J, Calzone L, Demongeot J, Kaufman M, Naldi A, Snoussi EH, Thieffry D (2013) On circuit functionality in boolean networks. Bull Math Biol 75(6):906–919PubMedCrossRefGoogle Scholar
  21. Cortassa S, Aon MA, Winslow RL, O’Rourke B (2004) A mitochondrial oscillator dependent on reactive oxygen species. Biophys J 87(3):2060–2073PubMedCentralPubMedCrossRefGoogle Scholar
  22. Cribbs JT, Strack S (2007) Reversible phosphorylation of drp1 by cyclic amp-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 8(10):939–944PubMedCentralPubMedCrossRefGoogle Scholar
  23. de Jong H (2002) Modeling and simulation of genetic regulatory systems: a literature review. J Comput Biol 9(1):67–103PubMedCrossRefGoogle Scholar
  24. Duvezin-Caubet S, Jagasia R, Wagener J, Hofmann S, Trifunovic A, Hansson A, Chomyn A, Bauer MF, Attardi G, Larsson NG, Neupert W, Reichert AS (2006) Proteolytic processing of opa1 links mitochondrial dysfunction to alterations in mitochondrial morphology. J Biol Chem 281(49):37,972–37,979CrossRefGoogle Scholar
  25. Escobar-Henriques M, Langer T (2006) Mitochondrial shaping cuts. Biochim Biophys Acta 1763(5-6):422–429PubMedCrossRefGoogle Scholar
  26. Ferrell JE Jr (2002) Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr Opin Cell Biol 14(2):140–148PubMedCrossRefGoogle Scholar
  27. Figge MT, Reichert AS, Meyer-Hermann M, Osiewacz HD (2012) Deceleration of fusion–fission cycles improves mitochondrial quality control during aging. PLoS Comput Biol 8(6):e1002,576CrossRefGoogle Scholar
  28. Figueiredo PA, Mota MP, Appell HJ, Duarte JA (2008) The role of mitochondria in aging of skeletal muscle. Biogerontology 9(2):67–84PubMedCrossRefGoogle Scholar
  29. Finkel T, Serrano M, Blasco MA (2007) The common biology of cancer and ageing. Nature 448(7155):767–774PubMedCrossRefGoogle Scholar
  30. Fridlyand LE, Philipson LH (2010) Glucose sensing in the pancreatic beta cell: a computational systems analysis. Theor Biol Med Model 7:15PubMedCentralPubMedCrossRefGoogle Scholar
  31. Fudenberg D, Tirole J (1991) Game theory. The MIT Press, CambridgeGoogle Scholar
  32. Galloway CA, Lee H, Yoon Y (2012) Mitochondrial morphology-emerging role in bioenergetics. Free Radic Biol Med 53(12):2218–2228PubMedCrossRefGoogle Scholar
  33. Gao CL, Liu GL, Liu S, Chen XH, Ji CB, Zhang CM, Xia ZK, Guo XR (2011) Overexpression of pgc-1 improves insulin sensitivity and mitochondrial function in 3t3-l1 adipocytes. Mol Cell Biochem 353(1-2):215–223PubMedCrossRefGoogle Scholar
  34. Giedt RJ, Pfeiffer DR, Matzavinos A, Kao CY, Alevriadou BR (2012) Mitochondrial dynamics and motility inside living vascular endothelial cells: role of bioenergetics. Ann Biomed Eng 40(9):1903–1916PubMedCentralPubMedCrossRefGoogle Scholar
  35. Goldbeter A (1991) A minimal cascade model for the mitotic oscillator involving cyclin and cdc2 kinase. Proc Natl Acad Sci USA 88(20):9107–9111PubMedCrossRefGoogle Scholar
  36. Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13(5):589–598PubMedCentralPubMedCrossRefGoogle Scholar
  37. Gonze D, Bernard S, Waltermann C, Kramer A, Herzel H (2005) Spontaneous synchronization of coupled circadian oscillators. Biophys J 89(1):120–129PubMedCentralPubMedCrossRefGoogle Scholar
  38. Harman D (1972) The biologic clock: The mitochondria?. J Am Geriatr Soc 20(4):145–147PubMedGoogle Scholar
  39. Hekimi S, Lapointe J, Wen Y (2011) Taking a “good” look at free radicals in the aging process. Trends Cell Biol 21(10):569–576PubMedCrossRefGoogle Scholar
  40. Heuett WJ, Periwal V (2010) Autoregulation of free radicals via uncoupling protein control in pancreatic beta-cell mitochondria. Biophys J 98(2):207–217PubMedCentralPubMedCrossRefGoogle Scholar
  41. Huang P, Galloway CA, Yoon Y (2011) Control of mitochondrial morphology through differential interactions of mitochondrial fusion and fission proteins. PLoS One 6(5):e20,655CrossRefGoogle Scholar
  42. Ishihara N, Fujita Y, Oka T, Mihara K (2006) Regulation of mitochondrial morphology through proteolytic cleavage of opa1. EMBO J 25(13):2966–2977PubMedCrossRefGoogle Scholar
  43. Izhikevich EM (2003) Simple model of spiking neurons. IEEE Trans Neural Netw 14(6):1569–1572PubMedCrossRefGoogle Scholar
  44. Jahani-Asl A, Slack RS (2007) The phosphorylation state of drp1 determines cell fate. EMBO Rep 8(10):912–913PubMedCentralPubMedCrossRefGoogle Scholar
  45. Jendrach M, Pohl S, Vth M, Kowald A, Hammerstein P, Bereiter-Hahn J (2005) Morpho-dynamic changes of mitochondria during ageing of human endothelial cells. Mech Ageing Dev 126(6-7):813–821PubMedCrossRefGoogle Scholar
  46. Jeneson JAL, Schmitz JPJ, van den Broek NMA, van Riel NAW, Hilbers PAJ, Nicolay K, Prompers JJ (2009) Magnitude and control of mitochondrial sensitivity to adp. Am J Physiol Endocrinol Metab 297(3):E774–E784PubMedCrossRefGoogle Scholar
  47. Johnston IG, Gaal B, Neves RPd, Enver T, Iborra FJ, Jones NS (2012) Mitochondrial variability as a source of extrinsic cellular noise. PLoS Comput Biol 8(3):e1002,416CrossRefGoogle Scholar
  48. Kaplan D, Glass L (1995) Understanding nonlinear dynamics. Springer, New YorkCrossRefGoogle Scholar
  49. Kirkwood TBL (2005) Understanding the odd science of aging. Cell 120(4):437–447PubMedCrossRefGoogle Scholar
  50. Kowald A, Kirkwood TB (2000) Accumulation of defective mitochondria through delayed degradation of damaged organelles and its possible role in the ageing of post-mitotic and dividing cells. J Theor Biol 202(2):145–160PubMedCrossRefGoogle Scholar
  51. Kowald A, Kirkwood TBL (2011) Evolution of the mitochondrial fusion–fission cycle and its role in aging. Proc Natl Acad Sci USA 108(25):10,237–10,242CrossRefGoogle Scholar
  52. Kowald A, Lehrach H, Klipp E (2006) Alternative pathways as mechanism for the negative effects associated with overexpression of superoxide dismutase. J Theor Biol 238(4):828–840PubMedCrossRefGoogle Scholar
  53. Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA (2005) Mitochondrial dna mutations, oxidative stress, and apoptosis in mammalian aging. Science 309(5733):481–484PubMedCrossRefGoogle Scholar
  54. Kurz FT, Aon MA, O’Rourke B, Armoundas AA (2010) Spatio-temporal oscillations of individual mitochondria in cardiac myocytes reveal modulation of synchronized mitochondrial clusters. Proc Natl Acad Sci USA 107(32):14,315–14,320CrossRefGoogle Scholar
  55. Legewie S, Blüthgen N, Herzel H (2006) Mathematical modeling identifies inhibitors of apoptosis as mediators of positive feedback and bistability. PLoS Comput Biol 2(9):e120PubMedCentralPubMedCrossRefGoogle Scholar
  56. Liu X, Weaver D, Shirihai O, Hajnczky G (2009) Mitochondrial ‘kiss-and-run’: interplay between mitochondrial motility and fusion–fission dynamics. EMBO J 28(20):3074–3089PubMedCrossRefGoogle Scholar
  57. Ma W, Trusina A, El-Samad H, Lim WA, Tang C (2009) Defining network topologies that can achieve biochemical adaptation. Cell 138(4):760–773PubMedCentralPubMedCrossRefGoogle Scholar
  58. Martinez-Outschoorn UE, Pestell RG, Howell A, Tykocinski ML, Nagajyothi F, Machado FS, Tanowitz HB, Sotgia F, Lisanti MP (2011) Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and achilles’ heel of tumor cells. Cell Cycle 10(24):4208–4216PubMedCrossRefGoogle Scholar
  59. Mazzoni C, Falcone C (2011) The importance of mitochondrial fusion in aging. Cell Cycle 10(21):3631PubMedCrossRefGoogle Scholar
  60. McBride HM, Neuspiel M, Wasiak S (2006) Mitochondria: more than just a powerhouse. Curr Biol 16(14):R551–R560PubMedCrossRefGoogle Scholar
  61. McCarthy N (2012) Mitochondria: getting together. Nat Rev Cancer 12(10):661PubMedCrossRefGoogle Scholar
  62. McDougal DB, Osborn LA (1976) Post-tetanic hyperpolarization, sodium-potassium-activated adenosine triphosphatase and high energy phosphate levels in garfish olfactory nerve. J Physiol 256(1):41–60PubMedGoogle Scholar
  63. Meinhardt H (2009) Models for the generation and interpretation of gradients. Cold Spring Harb Perspect Biol 1(4):a001,362CrossRefGoogle Scholar
  64. Miquel J (1991) An integrated theory of aging as the result of mitochondrial-DNA mutation in differentiated cells. Arch Gerontol Geriatr 12(2-3):99–117PubMedCrossRefGoogle Scholar
  65. Mouli PK, Twig G, Shirihai OS (2009) Frequency and selectivity of mitochondrial fusion are key to its quality maintenance function. Biophys J 96(9):3509–3518PubMedCentralPubMedCrossRefGoogle Scholar
  66. Novák B, Tyson JJ (2008) Design principles of biochemical oscillators. Nat Rev Mol Cell Biol 9(12):981–991PubMedCentralPubMedCrossRefGoogle Scholar
  67. Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148(6):1145–1159PubMedCrossRefGoogle Scholar
  68. Passarino G, Rose G, Bellizzi D (2010) Mitochondrial function, mitochondrial dna and ageing: a reappraisal. Biogerontology 11(5):575–588PubMedCrossRefGoogle Scholar
  69. Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, Wappler I, Birket MJ, Harold G, Schaeuble K, Birch-Machin MA, Kirkwood TBL, von Zglinicki T (2007) Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 5(5):e110PubMedCentralPubMedCrossRefGoogle Scholar
  70. Pellegrini L, Scorrano L (2007) A cut short to death: parl and opa1 in the regulation of mitochondrial morphology and apoptosis. Cell Death Differ 14(7):1275–1284PubMedCrossRefGoogle Scholar
  71. Pomerening JR, Kim SY, Ferrell JE Jr (2005) Systems-level dissection of the cell-cycle oscillator: bypassing positive feedback produces damped oscillations. Cell 122(4):565–578PubMedCrossRefGoogle Scholar
  72. Poovathingal SK, Gruber J, Halliwell B, Gunawan R (2009) Stochastic drift in mitochondrial dna point mutations: a novel perspective ex silico. PLoS Comput Biol 5(11):e1000,572CrossRefGoogle Scholar
  73. Rizzuto R, Marchi S, Bonora M, Aguiari P, Bononi A, De Stefani D, Giorgi C, Leo S, Rimessi A, Siviero R, Zecchini E, Pinton P (2009) Ca(2+) transfer from the er to mitochondria: when, how and why. Biochim Biophys Acta 1787(11):1342–1351PubMedCentralPubMedCrossRefGoogle Scholar
  74. Savageau MA, Fasani RA (2009) Qualitatively distinct phenotypes in the design space of biochemical systems. FEBS Lett 583(24):3914–3922PubMedCentralPubMedCrossRefGoogle Scholar
  75. Savageau MA, Coelho PMBM, Fasani RA, Tolla DA, Salvador A (2009) Phenotypes and tolerances in the design space of biochemical systems. Proc Natl Acad Sci U S A 106(16):6435–6440PubMedCentralPubMedCrossRefGoogle Scholar
  76. Seo AY, Joseph AM, Dutta D, Hwang JCY, Aris JP, Leeuwenburgh C (2010) New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci 123(Pt 15):2533–2542PubMedCrossRefGoogle Scholar
  77. Serasinghe MN, Yoon Y (2008) The mitochondrial outer membrane protein hfis1 regulates mitochondrial morphology and fission through self-interaction. Exp Cell Res 314(19):3494–3507PubMedCentralPubMedCrossRefGoogle Scholar
  78. Shutt T, Geoffrion M, Milne R, McBride HM (2012) The intracellular redox state is a core determinant of mitochondrial fusion. EMBO Rep 13(10):909–915PubMedCentralPubMedCrossRefGoogle Scholar
  79. Spencer SL, Sorger PK (2011) Measuring and modeling apoptosis in single cells. Cell 144(6):926–939PubMedCentralPubMedCrossRefGoogle Scholar
  80. Strauss W (1992) Partial differential equations: an introduction. Wiley, New YorkGoogle Scholar
  81. Suen DF, Norris KL, Youle RJ (2008) Mitochondrial dynamics and apoptosis. Genes Dev 22(12):1577–1590PubMedCrossRefGoogle Scholar
  82. Sukhorukov VM, Dikov D, Reichert AS, Meyer-Hermann M (2012) Emergence of the mitochondrial reticulum from fission and fusion dynamics. PLoS Comput Biol 8(10):e1002,745CrossRefGoogle Scholar
  83. Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K (2007) Mitotic phosphorylation of dynamin-related gtpase drp1 participates in mitochondrial fission. J Biol Chem 282(15):11,521–11,529CrossRefGoogle Scholar
  84. Tretter L, Chinopoulos C, Adam-Vizi V (1997) Enhanced depolarization-evoked calcium signal and reduced [atp]/[adp] ratio are unrelated events induced by oxidative stress in synaptosomes. J Neurochem 69(6):2529–2537PubMedCrossRefGoogle Scholar
  85. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlf S, Oldfors A, Wibom R, Trnell J, Jacobs HT, Larsson NG (2004) Premature ageing in mice expressing defective mitochondrial-DNA polymerase. Nature 429(6990):417–423PubMedCrossRefGoogle Scholar
  86. Turing AM (1990) The chemical basis of morphogenesis. 1953. Bull Math Biol 52(1–2):153–97; discussion 119–52Google Scholar
  87. Twig G, Elorza A, Molina AJA, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27(2):433–446PubMedCrossRefGoogle Scholar
  88. Tyson JJ, Albert R, Goldbeter A, Ruoff P, Sible J (2008) Biological switches and clocks. J R Soc Interface 5(Suppl 1):S1–S8PubMedCentralPubMedCrossRefGoogle Scholar
  89. Ullah M, Wolkenhauer O (2011) Stochastic approaches for systems biology. Springer, New YorkCrossRefGoogle Scholar
  90. Veening JW, Smits WK, Kuipers OP (2008) Bistability, epigenetics, and bet-hedging in bacteria. Annu Rev Microbiol 62:193–210PubMedCrossRefGoogle Scholar
  91. Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283(5407):1482–1488PubMedCrossRefGoogle Scholar
  92. Wallach A, Eytan D, Marom S, Meir R (2008) Selective adaptation in networks of heterogeneous populations: model, simulation, and experiment. PLoS Comput Biol 4(2):e29PubMedCentralPubMedCrossRefGoogle Scholar
  93. Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11(12):872–884PubMedCrossRefGoogle Scholar
  94. Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337(6098):1062–1065PubMedCrossRefGoogle Scholar
  95. Zorzano A, Liesa M, Palacn M (2009) Role of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes. Int J Biochem Cell Biol 41(10):1846–1854PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Anuradha Chauhan
    • 1
  • Julio Vera
    • 1
  • Olaf Wolkenhauer
    • 1
  1. 1.Department of Systems Biology and BioinformaticsUniversity of RostockRostockGermany

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