The dynamic life of the glycogen granule

Abstract

Glycogen, the primary storage form of glucose, is a rapid and accessible form of energy that can be supplied to tissues on demand. Each glycogen granule, or "glycosome," is considered an independent metabolic unit composed of a highly branched polysaccharide and various proteins involved in its metabolism. In this Minireview, we review the literature to follow the dynamic life of a glycogen granule in a multicompartmentalized system, i.e. the cell, and how and where glycogen granules appear and the factors governing its degradation. A better understanding of the importance of cellular compartmentalization as a regulator of glycogen metabolism is needed to unravel its role in brain energetics.

Keywords: actin; carbohydrate; carbohydrate biosynthesis; cell compartmentalization; endoplasmic reticulum (ER); glycogen; glycogenolysis; protein complex; sarcoplasmic reticulum (SR).

Figure 1.

Glycogen granule and the actin-rich spherical structures: EM observations. Analysis of glycogen granules by transmission EM has led to the identification of three structural entities: the γ-particle, the β- granule, and the α-granule (A). The γ-particle is highly electrodense after lead and uranyl acetate staining visualized as black clusters in the magnified arrow-marked glycogen granules (top-right corner) (B and C). The β- granule includes the carbohydrate polymer and the bound γ-particles, and the α-granule is composed of several β-granules bound via a protein backbone rich in disulfide bonds. At the start of glycogen re-synthesis after severe storage depletion, actin-rich spherical structures form (37), which in skeletal muscle are visualized by transmission EM as electrodense structures at the I-band of the sarcomeres in close proximity to the sarcoplasmic reticulum and transverse tubuli (D–G, white arrows). Scale bars, B, 250 nm; C and F, 200 nm; and D, E, and G, 500 nm.

Figure 2.

Life of a glycogen granule: birth to maturity. The start of a newly synthesized glycogen granule results from the coordinated dimerization and autoglycosylation of GN (A). GN glycosylation is believe to occur in the following two steps: intermolecular glycosylation as the transfer of 1–2 glucose units to tyrosine 194 (Tyr-194) from the other GN, and subsequent intramolecular glycosylation resulting in the elongation of the primer chain by the transfer of 7–16 glucose residues (B). Further elongation of the primer chain involves the coordinated action of glycogen synthase (GS) and glycogen-branching enzyme (GBE), adding glucose residues to the granule through α-1,4-linkage (B) and α-1,6-linkage (C), respectively. GN binds to actin filaments for the start of glycogen synthesis (D), and in situations of severe low glycogen levels, the formation of spherical actin-rich cellular structures (E) in which glycogen re-synthesis machinery gathers has been reported in several cell types. As glycogen granules mature, it may be released to the cytosol as an unbound acid-soluble glycogen granule (F), less metabolically active and ranging in size from 20 to 30 nm (G).

Figure 3.

Life of a glycogen granule: partial and complete degradation. Glycogen granules can be utilized by cytosolic degradation or by lysosomal degradation. Cytosolic glycogenolysis has been associated with the endoplasmic and sarcoplasmic reticulum, where the glycogenolytic complex, formed by glycogen phosphorylase (GP) and phosphorylase kinase (PhK), links glycogen utilization with calcium-ATPase (A). The coordinated action of GP and glycogen-debranching enzyme (GDE) results in the release of glucose 1-phosphate (Glc-1-P) and glucose (Glc), which are converted to glucose 6-phosphate (Glc-6-P) by phosphoglucomutase and hexokinase, respectively. Glc-6-P will either be used as substrate for glycolysis or, in gluconeogenic tissues, will enter the ER/SR through a glucose 6-phosphate transporter (Glc-6-PT) and converted to Glc by glucose-6-phosphatase (Glc-6-Pase) (B). The mechanisms by which glycogen granules are tagged for lysosomal degradation remain elusive; however, evidence indicates that phosphorylation of glycogen granules may play a role. Increased glycogen phosphorylation has been associated with increased branching points and solubility (C), whereas increases in glycogen phosphorylation are associated with lower branching degree and solubility (D). Binding and phosphorylation of laforin leads to malin recruitment, which could result in ubiquitination of glycogen-bound proteins directing them toward proteasome degradation (E). However, the starch binding domain 1 (Stbd-1) will bind to less branched glycogen granules tagging them for lysosomal degradation (F).