bims-glecem 2022-12-04 papers

Issue of 2022‒12‒04
four papers selected by
Dipsikha Biswas, Københavns Universitet

Front Pediatr. 2022 ;10 999596

Glycogen storage disease type Ia misdiagnosed as multiple acyl-coenzyme A dehydrogenase deficiency by mass spectrometry.

Juan Du, Li-Min Dou, Yong-Hong Jin, Qing-Fen Wen, Ya-Fen Lin, Jian-She Wang.

Objective: To report a case of glycogen storage disease (GSD) type Ia misdiagnosed as multiple acyl-coenzyme a dehydrogenase deficiency (MADD) by mass spectrometry.Methods: A 7 months old boy was admitted to our hospital for elevated transaminase levels lasting more than 1 month. His blood biochemistry showed hypoglycemia, metabolic acidosis, hyperlipidemia, elevated lactate and uric acid, elevated alanine amino transferase (ALT), aspartate amino transaminase (AST) and gamma-glutamyl transferase (GGT). Mass spectrometry analysis of blood and urine showed elevated blood acylcarnitines and dicarboxylic aciduria, indicating multiple acyl-coenzyme A dehydrogenase deficiency. Sanger sequencing of all exons of glucose-6-phosphatase (G6Pase) and electronic transfer flavoprotein dehydrogenase (ETFDH) was performed for the patient and his parents.
Results: Coding and flanking sequences of the G6Pase gene detected two heterozygous single base substitutions in the boy. One variant was in exon 1 (c.209G > A), Which was also detected in the father. Another was in exon 5 (c.648G > T), which was detected in the mother. Coding and flanking sequences of the ETFDH gene revealed no pathogenic/likely pathogenic variants in the boy.
Conclusion: GSD Ia can manifest elevated blood acyl carnitines and dicarboxylic aciduria which were the typical clinical manifestations of MADD. So the patient with clinical manifestations similar to MADD is in need of differential diagnosis for GSD Ia. Genetic testing is helpful to confirming the diagnosis of inherited metabolic diseases.

Keywords: gene variant; glucose-6-Phosphatase; glycogen storage disease type Ia; mass spectrometry; multiple acyl- coenzyme a dehydrogenase deficiency

DOI: https://doi.org/10.3389/fped.2022.999596

Front Cell Infect Microbiol. 2022 ;12 938286

Exogenous glycogen utilization effects the transcriptome and pathogenicity of Streptococcus suis serotype 2.

Mei-Fang Tan, Jia Tan, Fan-Fan Zhang, Hai-Qin Li, Hua-Yuan Ji, Shao-Pei Fang, Cheng-Cheng Wu, Yu-Ling Rao, Yan-Bin Zeng, Qun Yang.

Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that causes severe infections in humans and the swine industry. Acquisition and utilization of available carbon sources from challenging host environments is necessary for bacterial pathogens to ensure growth and proliferation. Glycogen is abundant in mammalian body and may support the growth of SS2 during infection in hosts. However, limited information is known about the mechanism between the glycogen utilization and host adaptation of SS2. Here, the pleiotropic effects of exogenous glycogen on SS2 were investigated through transcriptome sequencing. Analysis of transcriptome data showed that the main basic metabolic pathways, especially the core carbon metabolism pathways and virulence-associated factors, of SS2 responded actively to glycogen induction. Glycogen induction led to the perturbation of the glycolysis pathway and citrate cycle, but promoted the pentose phosphate pathway and carbohydrate transport systems. Extracellular glycogen utilization also promoted the mixed-acid fermentation in SS2 rather than homolactic fermentation. Subsequently, apuA, a gene encoding the unique bifunctional amylopullulanase for glycogen degradation, was deleted from the wild type and generated the mutant strain ΔapuA. The pathogenicity details of the wild type and ΔapuA cultured in glucose and glycogen were investigated and compared. Results revealed that the capsule synthesis or bacterial morphology were not affected by glycogen incubation or apuA deletion. However, extracellular glycogen utilization significantly enhanced the hemolytic activity, adhesion and invasion ability, and lethality of SS2. The deletion of apuA also impaired the pathogenicity of bacteria cultured in glucose, indicating that ApuA is indeed an important virulence factor. Our results revealed that exogenous glycogen utilization extensively influenced the expression profile of the S. suis genome. Based on the transcriptome response, exogenous glycogen utilization promoted the carbon adaption and pathogenicity of SS2.

Keywords: ApuA; Streptococcus suis; carbon metabolism; exogenous glycogen; pathogenicity; virulence factor

DOI: https://doi.org/10.3389/fcimb.2022.938286

J Exp Bot. 2022 Dec 01. pii: erac474. [Epub ahead of print]

Stress response requires efficient glycogen and central carbon metabolism connection by phosphoglucomutases in cyanobacteria.

Pablo Ortega-Martínez, Miguel Roldán, Sandra Díaz-Troya, Francisco J Florencio.

Glycogen and starch are the main storage polysaccharides, acting as a source of carbon and energy when necessary. Interconversion of glucose-1-phosphate and glucose-6-phosphate by phosphoglucomutases connects the metabolism of these polysaccharides with central carbon metabolism. However, knowledge about how this connection affects the ability of cells to cope with environmental stresses is still scarce. The cyanobacterium Synechocystis sp. PCC 6803 has two enzymes with phosphoglucomutase activity, PGM (phosphoglucomutase) and PMM/PGM (phosphomannomutase/phosphoglucomutase). In this work, we generated a null mutant of PGM (∆PGM) that exhibits very reduced phosphoglucomutase activity (1% of wild type). Although this mutant accumulates moderate amounts of glycogen, its phenotype resembles that of glycogen-less mutants, including high-light sensitivity and altered response to nitrogen deprivation. Using an on/off arsenite promoter, we demonstrate that PMM/PGM is essential for growth and responsible for the remaining phosphoglucomutase activity in the ∆PGM strain. Furthermore, overexpression of PMM/PGM in the ∆PGM strain is enough to revoke the phenotype of this mutant. These results emphasize the importance of an adequate flux between glycogen and central carbon metabolism to maintain cellular fitness and indicate that although PGM is the main phosphoglucomutase activity, the phosphoglucomutase activity of PMM/PGM can substitute it when expressed at enough amount.

Keywords: cyanobacteria; environmental stress; glycogen; high light; nitrogen metabolism; phosphoglucomutase; phosphohexomutase

DOI: https://doi.org/10.1093/jxb/erac474

Mol Metab. 2022 Nov 28. pii: S2212-8778(22)00217-4. [Epub ahead of print] 101648

Low aerobic capacity in McArdle disease: a role for mitochondrial network impairment?

M Villarreal-Salazar, A Santalla, A Real-Martínez, G Nogales-Gadea, P L Valenzuela, C Fiuza-Luces, A L Andreu, J C Rodríguez-Aguilera, M A Martín, J Arenas, J Vissing, A Lucia, T O Krag, T Pinós.

BACKGROUND: McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO2peak)), a phenomenon traditionally attributed to reduced glycolytic flux and Krebs cycle anaplerosis. Here we hypothesized an additional role for muscle mitochondrial network alterations associated with massive intracellular glycogen accumulation.METHODS: We analyzed in depth mitochondrial characteristics--content, biogenesis, ultrastructure--and network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO2peak in patients (both sexes, N=145) and healthy controls (N=133).
RESULTS: Besides corroborating very poor VO2peak values in patients and impairment in muscle glycolytic flux, we found that, in McArdle muscle: (a) damaged fibers are likely those with a higher mitochondrial and glycogen content, which show major disruption of the three main cytoskeleton components--actin microfilaments, microtubules and intermediate filaments--thereby contributing to mitochondrial network disruption in skeletal muscle fibers; (b) there was an altered subcellular localization of mitochondrial fission/fusion proteins and of the sarcoplasmic reticulum protein calsequestrin--with subsequent alteration in mitochondrial dynamics/function; impairment in mitochondrial content/biogenesis; and (c) several OXPHOS-related complex proteins/activities were also affected.
CONCLUSIONS: In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses.

Keywords: McArdle disease; aerobic capacity; cytoskeleton and mitochondrial network; glycogen; skeletal muscle

DOI: https://doi.org/10.1016/j.molmet.2022.101648