Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy

Koutsifeli, Parisa; Varma, Upasna; Daniels, Lorna J.; Annandale, Marco; Li, Xun; Neale, Joshua P. H.; Hayes, Sarah H.; Weeks, Kate L.; S, James; Delbridge, L.; Mellor, Kimberley M.

doi:10.1016/j.jbc.2022.102093

Cited by 33 publications

(17 citation statements)

References 96 publications

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“…The specificity of degradation cargos makes selective autophagy play an essential role in physiology metabolism and modulating the pathogenesis, for which no alternative pathway can compensate [45,46]. Glycophagy is considered a form of selective autophagy, in which glycogen is sequestered within autophagosomes and degraded by GAA in lysosomes [47]. However, the specific role of a lysosomal pathway in glycogen degradation has not been investigated [48].…”

Section: Discussionmentioning

confidence: 99%

Defect in degradation of glycogenin‐exposed residual glycogen in lysosomes is the fundamental pathomechanism of Pompe disease

Zhang,

Liu,

Zhao

et al. 2024

The Journal of Pathology

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Pompe disease is a lysosomal storage disorder that preferentially affects muscles, and it is caused by GAA mutation coding acid alpha‐glucosidase in lysosome and glycophagy deficiency. While the initial pathology of Pompe disease is glycogen accumulation in lysosomes, the special role of the lysosomal pathway in glycogen degradation is not fully understood. Hence, we investigated the characteristics of accumulated glycogen and the mechanism underlying glycophagy disturbance in Pompe disease. Skeletal muscle specimens were obtained from the affected sites of patients and mouse models with Pompe disease. Histological analysis, immunoblot analysis, immunofluorescence assay, and lysosome isolation were utilized to analyze the characteristics of accumulated glycogen. Cell culture, lentiviral infection, and the CRISPR/Cas9 approach were utilized to investigate the regulation of glycophagy accumulation. We demonstrated residual glycogen, which was distinguishable from mature glycogen by exposed glycogenin and more α‐amylase resistance, accumulated in the skeletal muscle of Pompe disease. Lysosome isolation revealed glycogen‐free glycogenin in wild type mouse lysosomes and variously sized glycogenin in Gaa−/− mouse lysosomes. Our study identified that a defect in the degradation of glycogenin‐exposed residual glycogen in lysosomes was the fundamental pathological mechanism of Pompe disease. Meanwhile, glycogenin‐exposed residual glycogen was absent in other glycogen storage diseases caused by cytoplasmic glycogenolysis deficiencies. In vitro, the generation of residual glycogen resulted from cytoplasmic glycogenolysis. Notably, the inhibition of glycogen phosphorylase led to a reduction in glycogenin‐exposed residual glycogen and glycophagy accumulations in cellular models of Pompe disease. Therefore, the lysosomal hydrolysis pathway played a crucial role in the degradation of residual glycogen into glycogenin, which took place in tandem with cytoplasmic glycogenolysis. These findings may offer a novel substrate reduction therapeutic strategy for Pompe disease. © 2024 The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Defect in degradation of glycogenin‐exposed residual glycogen in lysosomes is the fundamental pathomechanism of Pompe disease

Zhang,

Liu,

Zhao

et al. 2024

The Journal of Pathology

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“…Several other glycogen-related proteins that also contain the LC3/GABARAP-interacting motif to incorporate the cargo into autophagosomes were identified in a proteomic analysis of the autophagy interaction network and in silico, such as glycogen-branching enzyme, glycogen phosphorylase, and the muscle form of glycogen synthase, but the presence of this motif does not guarantee the actual binding and anchoring of glycogen molecules to the autophagosomal membranes [103][104][105]. Interestingly, glycogen synthase was shown to regulate glycogen autophagy in skeletal muscle through its interaction with Atg8 protein in a chloroquine-induced Drosophila model of vacuolar myopathy [106].…”

Section: Glycogen Traffic To the Lysosomementioning

confidence: 99%

“…In this setting, the cells were shown to activate PPAR, AKT, and AMPK signaling pathways and to rewire their metabolic program to decrease glucose metabolism and increase fatty acid and glutamine metabolism [99]. These data indicate that glycophagy is a highly regulated process involved in maintaining cellular energy homeostasis [99] (reviewed in [105,111]).…”

Section: Glycogen Traffic To the Lysosomementioning

confidence: 99%

Failure of Autophagy in Pompe Disease

Do,

Meena,

Raben

2024

Biomolecules

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Autophagy is an evolutionarily conserved lysosome-dependent degradation of cytoplasmic constituents. The system operates as a critical cellular pro-survival mechanism in response to nutrient deprivation and a variety of stress conditions. On top of that, autophagy is involved in maintaining cellular homeostasis through selective elimination of worn-out or damaged proteins and organelles. The autophagic pathway is largely responsible for the delivery of cytosolic glycogen to the lysosome where it is degraded to glucose via acid α-glucosidase. Although the physiological role of lysosomal glycogenolysis is not fully understood, its significance is highlighted by the manifestations of Pompe disease, which is caused by a deficiency of this lysosomal enzyme. Pompe disease is a severe lysosomal glycogen storage disorder that affects skeletal and cardiac muscles most. In this review, we discuss the basics of autophagy and describe its involvement in the pathogenesis of muscle damage in Pompe disease. Finally, we outline how autophagic pathology in the diseased muscles can be used as a tool to fast track the efficacy of therapeutic interventions.

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“…Besides its role in lipid metabolism, autophagy also plays a significant role in hepatocyte carbohydrate metabolism by regulating glycogen breakdown[ 74 ]. The lysosomal α-acid glucosidase can hydrolyze glycogen and release free glucose[ 75 ].…”

Section: Autophagy In Hepatocytesmentioning

confidence: 99%

Cell-type specific role of autophagy in the liver and its implications in non-alcoholic fatty liver disease

Raza,

Rajak,

Singh

et al. 2023

World J Hepatol

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Autophagy, a cellular degradative process, has emerged as a key regulator of cellular energy production and stress mitigation. Dysregulated autophagy is a common phenomenon observed in several human diseases, and its restoration offers curative advantage. Non-alcoholic fatty liver disease (NAFLD), more recently renamed metabolic dysfunction-associated steatotic liver disease, is a major metabolic liver disease affecting almost 30% of the world population. Unfortunately, NAFLD has no pharmacological therapies available to date. Autophagy regulates several hepatic processes including lipid metabolism, inflammation, cellular integrity and cellular plasticity in both parenchymal (hepatocytes) and non-parenchymal cells (Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells) with a profound impact on NAFLD progression. Understanding cell type-specific autophagy in the liver is essential in order to develop targeted treatments for liver diseases such as NAFLD. Modulating autophagy in specific cell types can have varying effects on liver function and pathology, making it a promising area of research for liver-related disorders. This review aims to summarize our present understanding of cell-type specific effects of autophagy and their implications in developing autophagy centric therapies for NAFLD.

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Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy

Cited by 33 publications

References 96 publications

Defect in degradation of glycogenin‐exposed residual glycogen in lysosomes is the fundamental pathomechanism of Pompe disease

Defect in degradation of glycogenin‐exposed residual glycogen in lysosomes is the fundamental pathomechanism of Pompe disease

Failure of Autophagy in Pompe Disease

Cell-type specific role of autophagy in the liver and its implications in non-alcoholic fatty liver disease

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