bims-meglyc 2023-08-27 papers

Genes (Basel). 2023 Aug 04. pii: 1585. [Epub ahead of print]14(8):

Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG.

Anna N Ligezka, Rohit Budhraja, Yurika Nishiyama, Fabienne C Fiesel, Graeme Preston, Andrew Edmondson, Wasantha Ranatunga, Johan L K Van Hove, Jens O Watzlawik, Wolfdieter Springer, Akhilesh Pandey, Eva Morava, Tamas Kozicz.

Congenital disorders of glycosylation (CDG) and mitochondrial disorders are multisystem disorders with overlapping symptomatology. Pathogenic variants in the PMM2 gene lead to abnormal N-linked glycosylation. This disruption in glycosylation can induce endoplasmic reticulum stress, contributing to the disease pathology. Although impaired mitochondrial dysfunction has been reported in some CDG, cellular bioenergetics has never been evaluated in detail in PMM2-CDG. This prompted us to evaluate mitochondrial function and autophagy/mitophagy in vitro in PMM2 patient-derived fibroblast lines of differing genotypes from our natural history study. We found secondary mitochondrial dysfunction in PMM2-CDG. This dysfunction was evidenced by decreased mitochondrial maximal and ATP-linked respiration, as well as decreased complex I function of the mitochondrial electron transport chain. Our study also revealed altered autophagy in PMM2-CDG patient-derived fibroblast lines. This was marked by an increased abundance of the autophagosome marker LC3-II. Additionally, changes in the abundance and glycosylation of proteins in the autophagy and mitophagy pathways further indicated dysregulation of these cellular processes. Interestingly, serum sorbitol levels (a biomarker of disease severity) and the CDG severity score showed an inverse correlation with the abundance of the autophagosome marker LC3-II. This suggests that autophagy may act as a modulator of biochemical and clinical markers of disease severity in PMM2-CDG. Overall, our research sheds light on the complex interplay between glycosylation, mitochondrial function, and autophagy/mitophagy in PMM2-CDG. Manipulating mitochondrial dysfunction and alterations in autophagy/mitophagy pathways could offer therapeutic benefits when combined with existing treatments for PMM2-CDG.

Keywords: LC3-II autophagy marker; congenital disorders of glycosylation; glycoproteomics; mitophagy; phosphomannomutase 2 deficiency; proteomics; secondary suboptimal mitochondrial function

DOI: https://doi.org/10.3390/genes14081585

Mol Genet Metab. 2023 Aug 09. pii: S1096-7192(23)00312-8. [Epub ahead of print]140(3): 107682

Combined PMM2-CDG and hereditary fructose intolerance in a patient with mild clinical presentation.

Xinying Hong, Andrew C Edmondson, Alanna Strong, Daniel Pomerantz, Emma Michl, Gerard Berry, Miao He.

We report a patient with an extremely rare, combined diagnosis of PMM2-CDG and hereditary fructose intolerance (HFI). By comparing with other patients, under-galactosylation was identified as a feature of HFI. Fructose/sorbitol/sucrose restriction was initiated right afterwards. The patient is at the mild end of the PMM2-CDG spectrum, raising the question of sorbitol's role in the pathogenesis of PMM2-CDG and whether fructose/sorbitol/sucrose restriction could benefit other PMM2-CDG patients. Additionally, epalrestat, an emerging potential PMM2-CDG therapy, may benefit HFI patients.

Keywords: Consanguinity; Hereditary fructose intolerance; PMM2-CDG; Sorbitol; Under-galactosylation

DOI: https://doi.org/10.1016/j.ymgme.2023.107682

Am J Physiol Cell Physiol. 2023 Aug 21.

Hexosamine Biosynthetic Pathway and O-GlcNAc cycling of Glucose Metabolism in Brain Function and Disease.

Dong Yeol Kim, Jiwon Park, Inn-Oc Han.

Impaired brain glucose metabolism is considered a hallmark of brain dysfunction and neurodegeneration. Disruption of the hexosamine biosynthetic pathway (HBP) and subsequent O-linked N-acetylglucosamine (O-GlcNAc) cycling has been identified as an emerging link between altered glucose metabolism and defects in the brain. Myriads of cytosolic and nuclear proteins in the nervous system are modified at serine or threonine residues with a single N-acetylglucosamine (O-GlcNAc) molecule by O-GlcNAc transferase (OGT), which can be removed by β-N-acetylglucosaminidase (O-GlcNAcase, OGA). Homeostatic regulation of O-GlcNAc cycling is important for maintenance of normal brain activity. While significant evidence linking dysregulated HBP metabolism and aberrant O-GlcNAc cycling to induction or progression of neuronal diseases has been obtained, the issue of whether altered O-GlcNAcylation is causal in brain pathogenesis remains uncertain. Elucidation of the specific functions and regulatory mechanisms of individual O-GlcNAcylated neuronal proteins in both normal and diseased states may facilitate the identification of novel therapeutic targets for various neuronal disorders. The information presented in this review highlights the importance of HBP/O-GlcNAcylation in the neuronal system and summarizes the roles and potential mechanisms of O-GlcNAcylated neuronal proteins in maintaining normal brain function and initiation and progression of neurological diseases.

Keywords: Hexosamine biosynthetic pathway; Neurodegeneration; O-GlcNAcylation

DOI: https://doi.org/10.1152/ajpcell.00191.2023

Nat Metab. 2023 Aug;5(8): 1275-1289

The pentose phosphate pathway in health and disease.

Tara TeSlaa, Markus Ralser, Jing Fan, Joshua D Rabinowitz.

The pentose phosphate pathway (PPP) is a glucose-oxidizing pathway that runs in parallel to upper glycolysis to produce ribose 5-phosphate and nicotinamide adenine dinucleotide phosphate (NADPH). Ribose 5-phosphate is used for nucleotide synthesis, while NADPH is involved in redox homoeostasis as well as in promoting biosynthetic processes, such as the synthesis of tetrahydrofolate, deoxyribonucleotides, proline, fatty acids and cholesterol. Through NADPH, the PPP plays a critical role in suppressing oxidative stress, including in certain cancers, in which PPP inhibition may be therapeutically useful. Conversely, PPP-derived NADPH also supports purposeful cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) for signalling and pathogen killing. Genetic deficiencies in the PPP occur relatively commonly in the committed pathway enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency typically manifests as haemolytic anaemia due to red cell oxidative damage but, in severe cases, also results in infections due to lack of leucocyte oxidative burst, highlighting the dual redox roles of the pathway in free radical production and detoxification. This Review discusses the PPP in mammals, covering its roles in biochemistry, physiology and disease.

DOI: https://doi.org/10.1038/s42255-023-00863-2

Front Pediatr. 2023 ;11 1173787

Thiamine pyrophosphokinase deficiency: report of two Chinese cases and a literature review.

Dan Zhao, Ming Liu, Huafang Jiang, Tianyu Song, Chaolong Xu, Xin Duan, Ruoyu Duan, Han Xu, Zhimei Liu, Fang Fang.

Thiamine pyrophosphokinase (TPK) deficiency, is a rare autosomal recessive disorder of congenital metabolic dysfunction caused by variants in the TPK1 gene. TPK1 variants can lead to thiamine metabolic pathway obstacles, and its clinical manifestations are highly variable. We describe two cases of TPK deficiency with completely different phenotypes and different therapeutic effects, and 26 cases of previously reported were retrospectively reviewed to improve our understanding of the clinical and genetic features of the disease. Patients with TPK deficiency present with ataxia, dysarthria, dystonia, disturbance of consciousness, seizures, and other nervous system dysfunction. Different gene variant sites may lead to different clinical features and therapeutic effects. Gene analysis is important for the diagnosis of TPK deficiency caused by TPK1 variants, and thiamine supplementation has been the mainstay of treatment for TPK deficiency to date.

Keywords: TPK deficiency; TPK1; literature review; outcome predictors; thiamine pyrophosphokinase deficiency

DOI: https://doi.org/10.3389/fped.2023.1173787