Intracellular organelle networks: Understanding their organization and communication through systems-level modeling and analysis

Abstract

BACKGROUND: Membrane-bound intracellular organelles are biochemically distinct compartments used by eukaryotic cells for serving specialized physiological functions and organizing their internal environment. Recent studies revealed surprisingly extensive communication between these organelles and highlighted the network nature of their organization and communication. Since organization and communication of the organelles are carried out at the systems level through their networks, systems-level studies are essential for understanding the underlying mechanisms.

METHODS: We reviewed recent studies that used systems-level quantitative modeling and analysis to understand organization and communication of intracellular organelle networks.

RESULTS: We first review modeling and analysis studies on how fusion/fission and degradation/biogenesis, two essential and closely related classes of activities of individual organelles, collectively mediate the dynamic organization of their networks. We then turn to another important aspect of the dynamic organization of the organelle networks, namely how organelles are physically connected within their networks, a property referred to as the topology of the networks in mathematics, and summarize some of their distinct properties. Lastly, we briefly review modeling and analysis studies that aim to understand communication between different organelle networks, focusing on cellular calcium homeostasis as an example. We conclude with a brief discussion of future directions for research in this area.

CONCLUSIONS: Together, the reviewed studies provide critical insights into how diverse activities of individual organelles collectively mediate the organization and communication of their networks. They demonstrate the essential role of systems-level modeling and analysis in understanding complex behavior of such networks.

Key words： intracellular organelle; organelle network; organelle communication; network analysis; systems modeling

Acknowledgments

We thank members of the Yang research group for their valuable inputs and Kirill Kiselyov for thoughtful discussions. Q.B. acknowledges support of a John and Claire Bertucci Graduate Research Fellowship. G.Y. acknowledges support of National Science Foundation Faculty CAREER Award DBI-1149494.

Compliance with ethics guidelines

Qinle Ba and Ge Yang declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

References

1 Barabasi A L, Oltvai Z N (2004). Network biology: understanding the cell’s functional organization. Nat Rev Genet, 5(2): 101–113

2 Barrat A, Barthelemy M, Vespignani A (2008). Dynamic Processes on Complex Networks. Cambridge University Press.

3 Barsoum M J, Yuan H, Gerencser A A, Liot G, Kushnareva Y, Gräber S, Kovacs I, Lee W D, Waggoner J, Cui J, White A D, Bossy B, Martinou J C, Youle R J, Lipton S A, Ellisman M H, Perkins G A, Bossy‐Wetzel E (2006). Nitric oxide‐induced mitochondrial fission is regulated by dynamin‐related GTPases in neurons. EMBO J, 25(16): 3900–3911

4 Berridge M J, Bootman M D, Roderick H L (2003). Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol, 4(7): 517–529

5 Boccaletti S, Latora V, Moreno Y, Chavez M, Hwang D U (2006). Complex networks: Structure and dynamics. Phys Rep, 424(4-5): 175–308

6 Bonifacino J S, Glick B S (2004). The mechanisms of vesicle budding and fusion. Cell, 116(2): 153–166

7 Brandhorst D, Zwilling D, Rizzoli S O, Lippert U, Lang T, Jahn R (2006). Homotypic fusion of early endosomes: SNAREs do not determine fusion specificity. Proc Natl Acad Sci USA, 103(8): 2701–2706

8 Brini M, Calì T, Ottolini D, Carafoli E (2013). Intracellular Calcium Homeostasis and Signaling. In: Banci L, editor. Metallomics and the Cell. Springer Netherlands, Dordrecht. 119–168

9 Bucci C, Parton R G, Mather I H, Stunnenberg H, Simons K, Hoflack B, Zerial M (1992). The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell, 70(5): 715–728

10 Campbell G E H, Lowe W H, Fagan W F (2007). Living in the branches: population dynamics and ecological processes in dendritic networks. Ecol Lett, 10(2): 165–175

11 Carafoli E (1987). Intracellular calcium homeostasis. Annu Rev Biochem, 56(1): 395–433

12 Chan D C (2012). Fusion and fission: interlinked processes critical for mitochondrial health. Annu Rev Genet, 46(1): 265–287

13 Chan Y H M, Marshall W F (2012). How cells know the size of their organelles. Science, 337(6099): 1186–1189

14 Chen H, Chan D C (2009). Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases. Hum Mol Genet, 18(R2): R169–R176

15 Collins T J, Berridge M J, Lipp P, Bootman M D (2002). Mitochondria are morphologically and functionally heterogeneous within cells. EMBO J, 21(7): 1616–1627

16 Csordás G, Várnai P, Golenár T, Roy S, Purkins G, Schneider T G, Balla T, Hajnóczky G (2010). Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell, 39(1): 121–132

17 Cui J, Kaandorp J A (2006). Mathematical modeling of calcium homeostasis in yeast cells. Cell Calcium, 39(4): 337–348

18 Dupont G, Falcke M, Kirk V, Sneyd J (2016). Models of Calcium Signaling. Springer International Publishing

19 Elbaz Y, Schuldiner M (2011). Staying in touch: the molecular era of organelle contact sites. Trends Biochem Sci, 36(11): 616–623

20 Elmore S P, Qian T, Grissom S F, Lemasters J J (2001). The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J, 15(12): 2286–2287

21 Ferraro F, Kriston-Vizi J, Daniel J (2014). A two-tier Golgi-based control of organelle size underpins the functional plasticity of endothelial cells. Dev Cell, 29(3): 292–304

22 Figge M T, Reichert A S, Meyer-Hermann M, Osiewacz H D (2012). Deceleration of fusion-fission cycles improves mitochondrial quality control during aging. PLOS Comput Biol, 8(6): e1002576

23 Foret L, Jonathan E D, Villasenor R, Collinet C, Deutsch A, Brusch L, Zerial M, Kalaididis Y, Julicher E. (2012). A general theoretical framework to infer endosomal network dynamics from quantitative image analysis. Curr Biol, 22(15): 1381–1390

24 Frazier A E, Kiu C, Stojanovski D, Hoogenraad Nicholas J, Ryan Michael T (2006). Mitochondrial morphology and distribution in mammalian cells. Biol Chem, 387(12): 1551–1558

25 Frederick R L, Shaw J M (2007). Moving mitochondria: establishing distribution of an essential organelle. Traffic, 8(12): 1668–1675

26 Friedman J R, Lackner L L, West M, DiBenedetto J R, Nunnari J, Voeltz G K (2011). ER tubules mark sites of mitochondrial division. Science, 334(6054): 358–362

27 Gautreau A, Oguievetskaia K, Ungermann C (2014). Function and regulation of the endosomal fusion and fission machineries. Cold Spring Harb Perspect Biol, 6(3): a016832

28 Gomes L C, Benedetto G D, Scorrano L (2011). During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol, 13(5): 589–598

29 Grant B D, Donaldson J G (2009). Pathways and mechanisms of endocytic recycling. Nat Rev Mol Cell Biol, 10(9): 597–608

30 Helle S C J, Kanfer G, Kolar K, Lang A, Michel A H, Kornmann B (2013). Organization and function of membrane contact sites. Biochimica et Biophysica Acta (BBA) - Mol Cell Res, 1833(11): 2526–2541

31 Hoppins S, Lackner L, Nunnari J (2007). The machines that divide and fuse mitochondria. Annu Rev Biochem, 76(1): 751–780

32 Huotari J, Helenius A (2011). Endosome maturation. EMBO J, 30(17): 3481–3500

33 Jakobs S, Schauss A C, Hell S W (2003). Photoconversion of matrix targeted GFP enables analysis of continuity and intermixing of the mitochondrial lumen. FEBS Lett, 554(1-2): 194–200

34 Jendrach M, Pohl S, Vöth 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): 813–821

35 Kang J S, Tian J H, Pan P Y, Zald P, Li C, Deng C, Sheng Z H (2008). Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell, 132(1): 137–148

36 Karbowski M, Arnoult D, Chen H, Chan D C, Smith C L, Youle R J (2004). Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J Cell Biol, 164(4): 493–499

37 Klecker T, Böckler S, Westermann B (2014). Making connections: interorganelle contacts orchestrate mitochondrial behavior. Trends Cell Biol, 24(9): 537–545

38 Klumperman J (2011). Architecture of the mammalian Golgi. Cold Spring Harb Perspect Biol, 3(7): a005181

39 Knoblach B, Rachubinski R A (2015). Sharing the cell’s bounty – organelle inheritance in yeast. J Cell Sci, 128(4): 621–630

40 Korolchuk V I, Saiki S, Lichtenberg M, Siddiqi F H, Roberts E A, Imarisio S, Jahreiss L, Sarkar S, Futter M, Menzies F M, O’Kane C J, Deretic V, Rubinsztein D C (2011). Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol, 13(4): 453–460

41 Kuznetsov A V, Hermann M, Saks V, Hengster P, Margreiter R (2009). The cell-type specificity of mitochondrial dynamics. Int J Biochem Cell Biol, 41(10): 1928–1939

42 Kuznetsov A V, Margreiter R (2009). Heterogeneity of mitochondria and mitochondrial function within cells as another level of mitochondrial complexity. Int J Mol Sci, 10(4): 1911–1929

43 Labbé K, Murley A, Nunnari J (2014). Determinants and functions of mitochondrial behavior. Annu Rev Cell Dev Biol, 30(1): 357–391

44 Lee M C S, Miller E A, Goldberg J, Orci L, Schekman R (2004). Bi-directional protein transport between the ER and Golgi. Annu Rev Cell Dev Biol, 20(1): 87–123

45 Levine T P, Patel S (2016). Signalling at membrane contact sites: two membranes come together to handle second messengers. Curr Opin Cell Biol, 39: 77–83

46 Li X, Rydzewski N, Hider A, Zhang X, Yang J, Wang W, Gao Q, Cheng X, Xu H (2016). A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat Cell Biol, 18(4): 404–417

47 Liu X, Weaver D, Shirihai O, Hajnóczky G (2009). Mitochondrial ‘kiss‐and‐run’: interplay between mitochondrial motility and fusion–fission dynamics. EMBO J, 28(20): 3074–3089

48 Luzio J P, Pryor P R, Bright N A (2007). Lysosomes: fusion and function. Nat Rev Mol Cell Biol, 8(8): 622–632

49 Ma X, Gong N, Zhong L, Sun J, Liang X J (2016). Future of nanotherapeutics: targeting the cellular sub-organelles. Biomat, 97: 10–21

50 Marshall W F (2015). How cells measure length on subcellular scales. Trends Cell Biol, 25(12): 760–768

51 Martens S, McMahon H T (2008). Mechanisms of membrane fusion: disparate players and common principles. Nat Rev Mol Cell Biol, 9(7): 543–556

52 McNew J A, Sondermann H, Lee T, Stern M, Brandizzi F (2013). GTP-dependent membrane fusion. Annu Rev Cell Dev Biol, 29(1): 529–550

53 Means S, Smith A J, Shepherd J, Shadid J, Fowler J, Wojcikiewicz R J H, Mazel T, Smith G D, Wilson B S (2006). Reaction diffusion modeling of calcium dynamics with realistic ER geometry. Biophys J, 91(2): 537–557

54 Mizushima N (2007). Autophagy: process and function. Genes Dev, 21(22): 2861–2873

55 Mouli P K, Twig G, Shirihai O S (2009). Frequency and selectivity of mitochondrial fusion are key to its quality maintenance function. Biophys J, 96(9): 3509–3518

56 Murley A, Nunnari J (2016). The emerging network of mitochondria-organelle contacts. Mol Cell, 61(5): 648–653

57 Nakamura N, Wei J H, Seemann J (2012). Modular organization of the mammalian Golgi apparatus. Curr Opin Cell Biol, 24(4): 467–474

58 Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009). Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol, 10(7): 458–467

59 Namtame A, Chen S H (2016). Agent-based Modeling and Network Analysis. Oxford University Press

60 Newman M E J (2003). The structure and function of complex networks. SIAM Rev, 45(2): 167–256

61 Newman M E J 2010. Networks. Oxford University Press.

62 Ni H M, Williams J A, Ding W X (2015). Mitochondrial dynamics and mitochondrial quality control. Redox Biol, 4: 6–13

63 Nunnari J, Walter P (1996). Regulation of organelle biogenesis. Cell, 84(3): 389–394

64 Okamoto K, Shaw J M (2005). Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu Rev Genet, 39(1): 503–536

65 Palikaras K, Tavernarakis N (2014). Mitochondrial homeostasis: The interplay between mitophagy and mitochondrial biogenesis. Exp Gerontol, 56: 182–188

66 Patel P K, Shirihai O, Huang K C (2013). Optimal dynamics for quality control in spatially distributed mitochondrial networks. PLOS Comput Biol, 9(7): e1003108

67 Penny C J, Kilpatrick B S, Han J M, Sneyd J, Patel S (2014). A computational model of lysosome–ER Ca²⁺ microdomains. J Cell Sci, 127(13): 2934–2943

68 Phillips M J, Voeltz G K (2016). Structure and function of ER membrane contact sites with other organelles. Nat Rev Mol Cell Biol, 17(2): 69–82

69 Posakony J W, England J M, Attardi G (1977). Mitochondrial growth and division during the cell cycle in HeLa cells. J Cell Biol, 74(2): 468–491

70 Priault M, Salin B, Schaeffer J, Vallette F M, di Rago J P, Martinou J C (2005). Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast. Cell Death Differ, 12(12): 1613–1621

71 Prinz W A (2014). Bridging the gap: membrane contact sites in signaling, metabolism, and organelle dynamics. J Cell Biol, 205(6): 759–769

72 Rafelski S M, Viana M P, Zhang Y, Chan Y H M, Thorn K S, Yam P, Fung J C, Li H, Costa L D F, Marshall W F (2012). Mitochondrial network size scaling in budding yeast. Science, 338(6108): 822–824

73 Rambold A S, Kostelecky B, Elia N, Lippincott-Schwartz J (2011). Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA, 108(25): 10190–10195

74 Rink J, Ghigo E, Kalaidzidis Y, Zerial M (2005). Rab conversion as a mechanism of progression from early to late endosomes. Cell, 122(5): 735–749

75 Rohn J L, Patel J V, Neumann B, Bulkescher J, Mchedlishvili N, McMullan R C, Quintero O A, Ellenberg J, Baum B (2014). Myo19 ensures symmetric partitioning of mitochondria and coupling of mitochondrial segregation to cell division. Curr Biol, 24(21): 2598–2605

76 Rutter G A, Rizzuto R (2000). Regulation of mitochondrial metabolism by ER Ca²⁺ release: an intimate connection. Trends Biochem Sci, 25(5): 215–221

77 Scheckhuber C Q, Erjavec N, Tinazli A, Hamann A, Nystrom T, Osiewacz H D (2007). Reducing mitochondrial fission results in increased life span and fitness of two fungal ageing models. Nat Cell Biol, 9(1): 99–105

78 Schrader M, Godinho L F, Costello J, Islinger M (2015). The different facets of organelle interplay-an overview of organelle interactions. Front Cell Dev Biol, 3: 56

79 Sengupta D, Linstedt A D (2011). Control of organelle size: The Golgi complex. Annu Rev Cell Dev Biol, 27(1): 57–77

80 Sheng Z H (2014). Mitochondrial trafficking and anchoring in neurons: new insight and implications. J Cell Biol, 204(7): 1087–1098

81 Sheng Z H, Cai Q (2012). Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci, 13(2): 77–93

82 Shneyer B I, Ušaj M, Henn A (2016). Myo19 is an outer mitochondrial membrane motor and effector of starvation-induced filopodia. J Cell Sci, 129(3): 543–556

83 Sukhorukov V M, Dikov D, Reichert A S, Meyer-Hermann M (2012). Emergence of the mitochondrial reticulum from fission and fusion dynamics. PLOS Comput Biol, 8(10): e1002745

84 Sukhorukov V M, Meyer-Hermann M (2015). Structural heterogeneity of mitochondria induced by the microtubule cytoskeleton. Sci Rep, 5: 13924

85 Tam Z Y, Gruber J, Halliwell B, Gunawan R (2013). Mathematical modeling of the role of mitochondrial fusion and fission in mitochondrial DNA maintenance. PLoS One, 8(10): e76230

86 Torchilin V P (2006). Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu Rev Biomed Eng, 8(1): 343–375

87 Twig G, Elorza A, Molina A J A, Mohamed H, Wikstrom J D, Walzer G, Stiles L, Haigh S E, Katz S, Las G, Alroy J, Wu M, Py B F, Yuan J, Deeney J T, Corkey B E, Shirihai O S (2008a). Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J, 27(2): 433–446

88 Twig G, Hyde B, Shirihai O S (2008b). Mitochondrial fusion, fission and autophagy as a quality control axis: The bioenergetic view. Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1777(9): 1092–1097

89 Twig G, Liu X, Liesa M, Wikstrom J D, Molina A J A, Las G, Yaniv G, Hajnóczky G, Shirihai O S (2010). Biophysical properties of mitochondrial fusion events in pancreatic β-cells and cardiac cells unravel potential control mechanisms of its selectivity. Am J Physiol Cell Physiol, 299(2): C477–C487

90 Warren G, Wickner W (1996). Organelle inheritance. Cell, 84(3): 395–400

91 Westrate L M, Lee J E, Prinz W A, Voeltz G K (2015). Form follows function: The importance of endoplasmic reticulum shape. Annu Rev Biochem, 84(1): 791–811

92 Wikstrom J D, Twig G, Shirihai O S (2009). What can mitochondrial heterogeneity tell us about mitochondrial dynamics and autophagy? Int J Biochem Cell Biol, 41(10): 1914–1927

93 Youle R J, Narendra D P (2011). Mechanisms of mitophagy. Nat Rev Mol Cell Biol, 12(1): 9–14

94 Youle R J, van der Bliek A M (2012). Mitochondrial fission, fusion, and stress. Science, 337(6098): 1062–1065

95 Yu Y, Lee H C, Chen K C, Suhan J, Qiu M, Ba Q, Yang G (2016). Inner membrane fusion mediates spatial distribution of axonal mitochondria. Sci Rep, 6: 18981

96 Zhu X, Gerstein M, Snyder M (2007). Getting connected: analysis and principles of biological networks. Genes Dev, 21: 1010–1024