Pathology & Oncology Research

, Volume 24, Issue 4, pp 821–826 | Cite as

The ER – Glycogen Particle – Phagophore Triangle: A Hub Connecting Glycogenolysis and Glycophagy?

  • József MandlEmail author
  • Gábor Bánhegyi


Glycogen particle is an intracellular organelle, which serves as a carbohydrate reserve in various cells. The function of glycogen is not entirely known in several cell types. Glycogen can be mobilized for different purposes, which can be related to cellular metabolic needs, intracellular redox state, metabolic state of the whole organism depending on regulatory aspects and also on cell functions. Essentially there are two different ways of glycogen degradation localized in different cellular organelles: glycogenolysis or lysosomal breakdown by acid alpha-glucosidase. While glycogenolysis occurs in glycogen particles connected to endoplasmic reticulum membrane, glycogen particles can be also combined with phagophores forming autophagosomes. A subdomain of the endoplasmic reticulum membrane - omegasomes - are the sites for phagophore formation. Thus, three organelles, the endoplasmic reticulum, the phagophore and the glycogen particle forms a triangle in which glycogen degradation occurs. The physiological significance, molecular logic and regulation of the two different catabolic paths are summarized and discussed with special aspect on the role of glycogen particles in intracellular organelle homeostasis and on molecular pathology of the cell. Pathological aspects and some diseases connected to the two different degradation pathways of glycogen particles are also detailed.


Glycogen particle Glycogenolysis Endoplasmic reticulum Glycophagy Lysosome Phagophore 


  1. 1.
    Adeva-Andany MM, González-Lucán M, Donapetry-García C, Fernández-Fernández C, Ameneiros-Rodríguez E (2016) Glycogen metabolism in humans. Biochem Biophys Acta Clin 5:85–100Google Scholar
  2. 2.
    Duran J, Guinovart JJ (2015) Brain glycogen in health and disease. Mol Asp Med 46:70–77CrossRefGoogle Scholar
  3. 3.
    Csordas G, Varnai P, Golenar T, Roy S, Purkins G, Schneider TG, Balla T, Hajnoczky G (2010) Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell 39:121–132CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    de Brito OM, Scorrano L (2010) An intimate liaison: spatial organization of the endoplasmic reticulum-mitochondria relationship. EMBO J 29:2715–2723CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bánhegyi G, Mandl J (2001) The hepatic glycogenoreticular system. POR 7:107–110PubMedGoogle Scholar
  6. 6.
    Stapleton D, Nelson C, Parsawar K, McClain D, Gilbert-Wilson R, Barker E, Rudd B, Brown K, Hendrix W, O'Donnell P, Parker G (2010) Analysis of hepatic glycogen-associated proteins. Proteomics 10:2320–2329CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mandl J, Mészáros T, Bánhegyi G, Csala M (2013) Minireview: Endoplasmic reticulum stress: Control in protein, lipid, and signal homeostasis. Mol Endocrinol 27:384–393CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Csala M, Kereszturi É, Mandl J, Bánhegyi G (2012) The endoplasmic reticulum as the extracellular space inside the cell: role in protein folding and glycosylation. Antioxid Redox Signal 16:1100–1108CrossRefPubMedGoogle Scholar
  9. 9.
    Fawcett DW (1955) Observations on the cytology and electron microscopy of hepatic cells. J Natl Cancer Inst 15:1457–1503Google Scholar
  10. 10.
    Cardell RR Jr (1977) Smooth endoplasmic reticulum in rat hepatocytes during glycogen deposition and depletion. Int Rev Cytol 48:221–279CrossRefPubMedGoogle Scholar
  11. 11.
    Bánhegyi G, Garzó T, Antoni F, Mandl J (1988) Glycogenolysis – and not gluconeogenesis – is the source of UDP-glucuronic acid for glucuronidation. Biochim Biophys Acta 967:429–435CrossRefPubMedGoogle Scholar
  12. 12.
    Mandl J, Bánhegyi G, Kalapos M, Garzó T (1995) Increased oxidation and decreased conjugation of drugs in the liver caused by starvation. (review) Chem. Biol. Interactions 96:87–101Google Scholar
  13. 13.
    Helmika W, Wever R (1997) A new model for the membrane topology of glucose-6-phosphatase: the enzyme involved in von Gierke disease. FEBS Lett 409:317–319CrossRefGoogle Scholar
  14. 14.
    Pan CJ, Lei KJ, Annabi B et al (1998) Transmembrane topology of glucose-6-phosphatase. J Biol Chem 273:6144–6148CrossRefPubMedGoogle Scholar
  15. 15.
    Burchell G, Coughtrie MW (1989) UDP-glucuronosyltransferases. Pharmacol Ther 43:261–289CrossRefPubMedGoogle Scholar
  16. 16.
    Clarke DJ, Burchell G (1994) Conjugation-Deconjugation reactions in Drug Metabolism and Toxicity. In: Kauffman FC (ed) Handbook of Experimental Pharmacology, vol 112. Springer Verlag, Budapest, pp 3–43Google Scholar
  17. 17.
    Braun L, Garzo T, Mandl J, Banhegyi G (1994) Ascorbic acid synthesis is stimulated by enhanced glycogenolysis in murine liver. FEBS Lett 352:4–6CrossRefPubMedGoogle Scholar
  18. 18.
    Braun L, Csala M, Poussu A, Garzo T, Mandl J, Banhegyi G (1996) Glutathione depletion induces glycogenolysis dependent ascorbate synthesis in isolated murine hepatocytes. FEBS Lett 388:173–176CrossRefPubMedGoogle Scholar
  19. 19.
    Banhegyi G, Braun L, Csala M, Puskas F, Mandl J (1997) Ascorbate metabolism and its regulation in animals. Free Radic Biol Med 23:793–803CrossRefPubMedGoogle Scholar
  20. 20.
    Puskas F, Braun L, Csala M, Kardon T, Marcolongo P, Benedetti A, Mandl J, Banhegyi G (1998) Gulonolactone oxidase activity-dependent intravesicular glutathione oxidation in rat liver microsomes. FEBS Lett 430:293–296CrossRefPubMedGoogle Scholar
  21. 21.
    Dzyakanchuk AA, Balázs Z, Nashev LG, Amrein KE, Odermatt A (2009) 11beta-Hydroxysteroid dehydrogenase 1 reductase activity is dependent on a high ratio of NADPH/NADP(+) and is stimulated by extracellular glucose. Mol Cell Endocrinol 301:137–141CrossRefPubMedGoogle Scholar
  22. 22.
    Kereszturi É, Kálmán FS, Kardon T, Csala M, Bánhegyi G (2010) Decreased prereceptorial glucocorticoid activating capacity in starvation due to an oxidative shift of pyridine nucleotides in the endoplasmic reticulum. FEBS Lett 584:4703–4708CrossRefPubMedGoogle Scholar
  23. 23.
    Stapleton D, Nelson C, Parsawar K, Flores-Opazo M, McClain D, Parker G (2013) The 3T3-L1 adipocyte glycogen proteome. Proteome Sci 22:11CrossRefGoogle Scholar
  24. 24.
    Jiang S, Heller B, Tagliabracci VS, Zhai L, Irimia JM, DePaoli-Roach AA, Wells CD, Skurat AV, Roach PJ (2010) Starch binding domain-containing protein 1/genethonin 1 is a novel participant in glycogen metabolism. J Biol Chem 285:34960–34971CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Jiang S, Wells CD, Roach PJ (2011) Starch-binding domain-containing protein 1 (Stbd1) and glycogen metabolism: Identification of the Atg8 family interacting motif (AIM) in Stbd1 required for interaction with GABARAPL1. Biochem Biophys Res Commun 413:420–425CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Rong Y, McPhee CK, Deng S, Huang L, Chen L, Liu M, Tracy K, Baehrecke EH, Yu L, Lenardo MJ (2011) Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. Proc Natl Acad Sci 108:7826–7831CrossRefPubMedGoogle Scholar
  27. 27.
    Kotoulas OB, Phillips MJ (1971) Fine structural aspects of the mobilization of hepatic glycogen. I. Acceleration of glycogen breakdown. Am J Pathol 63:1–22PubMedPubMedCentralGoogle Scholar
  28. 28.
    Schiaffino S, Hanzlíková V (1972) Autophagic degradation of glycogen in skeletal muscles of the newborn rat. J Cell Biol 52:41–51CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kotoulas OB, Kalamidas SA, Kondomerkos DJ (2006) Glycogen autophagy in glucose homeostasis. Pathol Res Pract 202:631–638CrossRefPubMedGoogle Scholar
  30. 30.
    Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036CrossRefPubMedGoogle Scholar
  31. 31.
    Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169:425–434CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kalamidas SA, Kotoulas OB (2000) Glycogen autophagy in newborn rat hepatocytes. Histol Histopathol 15:1011–1018PubMedGoogle Scholar
  33. 33.
    Kondomerkos DJ, Kalamidas SA, Kotoulas OB, Hann AC (2005) Glycogen autophagy in the liver and heart of newborn rats. The effects of glucagon, adrenalin or rapamycin. Histol Histopathol 20:689–696PubMedGoogle Scholar
  34. 34.
    Mellor KM, Varma U, Stapleton DI, Delbridge LM (2014) Cardiomyocyte glycophagy is regulated by insulin and exposure to high extracellular glucose. Am J Physiol Heart Circ Physiol 306:H1240–H1245CrossRefPubMedGoogle Scholar
  35. 35.
    Ravikumar B, Stewart A, Kita H, Kato K, Duden R, Rubinsztein DC (2003) Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy. Hum Mol Genet 12:985–994CrossRefPubMedGoogle Scholar
  36. 36.
    Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, Griffiths G, Ktistakis NT et al (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182:685–701CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ahn HH, Oh Y, Lee H, Lee W, Chang JW, Pyo HK, Nah do H, Jung YK (2015) Identification of glucose-6-phosphate transporter as a key regulator functioning at the autophagy initiation step. FEBS Lett 589:2100–2109CrossRefPubMedGoogle Scholar
  38. 38.
    Chatelain F, Pegorier JP, Minassian C, Bruni N, Tarpin S, Girard J, Mithieux G (1998) Development and regulation of glucose-6-phosphatase gene expression in rat liver, intestine, and kidney: in vivo and in vitro studies in cultured fetal hepatocytes. Diabetes 47:882–889CrossRefPubMedGoogle Scholar
  39. 39.
    Froissart R, Piraud M, Boudjemline AM, Vianey-Saban C, Petit F, Hubert-Buron A, Eberschweiler PT, Gajdos V, Labrune P (2011) Glucose-6-phosphatase deficiency. Orphanet J Rare Dis 6:27CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Cavanagh JB (1999) Corpora-amylacea and the family of polyglucosan diseases. Brain Res Brain Res Rev 29:265–295CrossRefPubMedGoogle Scholar
  41. 41.
    Mandl J, Meszaros K, Antoni F, Spolarics Z, Garzo T (1982) Reversible inhibition of RNA synthesis and irreversible inhibition of protein synthesis by D-galactosamine in isolated mouse hepatocytes. Mol Cell Biochem 46:25–30CrossRefPubMedGoogle Scholar
  42. 42.
    Farah BL, Landau DJ, Sinha RA, Brooks ED, Wu Y, Fung SY, Tanaka T, Hirayama M, Bay BH, Koeberl DD, Yen PM (2016) Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency. J Hepatol 64:370–379CrossRefPubMedGoogle Scholar
  43. 43.
    Jeon JY, Lee H, Park J, Lee M, Park SW, Kim JS, Lee M, Cho B, Kim K, Choi AM, Kim CK, Yun M (2015) The regulation of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase by autophagy in low-glycolytic hepatocellular carcinoma cells. Biochem Biophys Res Commun 463:440–446CrossRefPubMedGoogle Scholar
  44. 44.
    Kaur J, Debnath J (2015) Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol 16:461–472CrossRefPubMedGoogle Scholar
  45. 45.
    Rousset M, Zweibaum A, Fogh J (1981) Presence of glycogen and growth-related variations in 58 cultured human tumor cell lines of various tissue origins. Cancer Res 41:1165–1170PubMedGoogle Scholar
  46. 46.
    Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V et al (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25:460–470CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell'antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, Kimmelman AC (2011) Pancreatic cancers require autophagy for tumor growth. Genes Dev 25:717–729CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Kapuy O, Vinod PK, Mandl J, Bánhegyi G (2013) A cellular stress-directed bistable switch controls the crosstalk between autophagy and apoptosis. Mol BioSyst 9:296–306CrossRefPubMedGoogle Scholar
  49. 49.
    Das CK, Mandal M, Kögel D (2018) Pro-survival autophagy and cancer cell resistance to therapy. Cancer Metastasis Rev.
  50. 50.
    Amaravadi R, Kimmelman AC, White E (2016) Recent insights into the function of autophagy in cancer. Genes Dev 30:1913–1930CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lashinger LM, O’Flanagan CH, Dunlap SM, Rasmussen AJ, Sweeney S, Guo JY, Lodi A, Tiziani S, White E, Hursting SD (2016) Starving cancer from the outside and inside: Separate and combined effects of calorie restriction and autophagy inhibition on Ras-driven tumors. Cancer Metab 4:18CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Dikic I (2017) Proteasomal and Autophagic Degradation Systems. Annu Rev Biochem 86:193–224CrossRefPubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2018

Authors and Affiliations

  1. 1.Department of Medical Chemistry, Molecular Biology and PathobiochemistrySemmelweis UniversityBudapestHungary

Personalised recommendations