bims-meglyc 2026-01-25 papers

Issue of 2026–01–25
five papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab. 2026 Jan 19. pii: S1096-7192(26)00020-X. [Epub ahead of print]147(3): 109737

Multi-omics analysis reveals ER stress as a main feature in two endothelial cell models of N-linked congenital disorders of glycosylation.

Karen Driesen, Veronika Holubová, Pedro Magalhães, Shauni Loopmans, Mainak Guharoy, Isabelle Meyts, Eva Morava, Bart Ghesquière, Peter Witters.

Glycosylation is one of the most important posttranslational modifications. When the glycosylation machinery is affected, this leads to a congenital disorder of glycosylation (CDG). CDG are a class of rare multisystemic diseases that often affect the endoplasmic reticulum (ER). Although vascular complications have been reported in CDG, the contribution of endothelial dysfunction to these phenotypes remains incompletely understood. Here, we evaluated the effect of glycosylation deficiency on endothelial dysfunction by generating two endothelial cell models using pharmacological inhibitors: tunicamycin (a well-known glycosylation inhibitor at the level of DPAGT1), and 2-deoxy-2-fluoro-D-mannose (FMan). This is a novel inhibitor that inhibits mannose and related sugar-phosphate metabolism. These cell models were subjected to transcriptomics, proteomics, and tracer metabolomics to pinpoint the pathways that are most affected across these different levels. Both transcriptomics and proteomics revealed ER stress as the top upregulated feature. This was functionally characterized by decreased cell growth, induced apoptosis, decreased cell migration, and induced an immune response. The barrier function of the cells was not affected. Here, we demonstrate that N-glycosylation deficiency triggers an ER stress response, contributing to endothelial dysfunction, and investigated ER stress mitigation as a potential therapeutic strategy for CDG.

Keywords: Congenital disorders of glycosylation; ER stress; Endothelial dysfunction; Omics

DOI: https://doi.org/10.1016/j.ymgme.2026.109737

J Inherit Metab Dis. 2026 Jan;49(1): e70133

CDG due to Defective Membrane Transporters: Update.

D Quelhas, C R Ferreira, J Jaeken.

Congenital disorders of glycosylation are genetic defects in the glycoprotein and glycolipid glycan assembly and attachment. Some 200 CDG have been reported since the first clinical description in 1980. Most CDG are enzymatic deficiencies, but 13 (6.5%) are defects in the ER, Golgi apparatus (GA), and plasma membrane transporters. This review provides an update on the clinical, biochemical, genetic, and therapeutic aspects of these disorders and on animal models. Defects in other cellular trafficking mechanisms have been excluded from this update.

DOI: https://doi.org/10.1002/jimd.70133

J Inherit Metab Dis. 2026 Jan;49(1): e70136

GMPPB-CDG Results in Lysosomal Dysfunction and Acid Alpha-Glucosidase Deficiency.

GDP-mannose pyrophosphorylase B (GMPPB) deficiency is a congenital disorder of glycosylation due to pathogenic variants of the GMPPB gene. GMPPB catalyzes GDP-mannose synthesis, an early step in multiple glycosylation pathways, including N-glycosylation, O-mannosylation, C-mannosylation, and glycosylphosphatidylinositol-anchor formation. In fibroblasts (N = 3), myoblasts (N = 4) and in muscle biopsies (N = 4) from a total of 7 GMPPB-deficient patients we found evidence of glycogen accumulation, both in cytosol and in lysosome-like vesicles, presence of heterogeneous storage material, and expansion of the lysosomal compartment. Due to the excess of glycogen in cells and tissues, we investigated acid alpha-glucosidase (GAA) in cultured GMPPB fibroblasts. GAA activity was reduced in GMPPB cells, with an impaired protein maturation and lysosomal localization. Incubation of cells with human recombinant GAA (rhGAA), that is fully glycosylated, showed complete correction of GAA activity, normal processing and lysosomal trafficking, with complete clearance of glycogen storage. These results suggest a secondary impairment of specific lysosomal functions in GMPPB deficiency and add information on the complexity of the pathophysiology of this disorder.

Keywords: GDP‐mannose pyrophosphorylase B deficiency; Pompe disease; acid alpha‐glucosidase; congenital disorders of glycosylation; lysosomal storage diseases

DOI: https://doi.org/10.1002/jimd.70136

Biochem Biophys Rep. 2026 Mar;45 102427

Mammalian fatty acid synthase and O-GlcNAc transferase preferentially interact via their respective N-terminal regions.

Dimitri Vanauberg, Céline Schulz, Guillaume Brysbaert, Nessim Raouraoua, Peggy Mistarz-Gruau, Marc F Lensink, Anne-Sophie Vercoutter-Edouart, Tony Lefebvre.

Fatty Acid Synthase (FASN) is a central enzyme in the de novo lipogenesis pathway. By producing fatty acids, FASN is implicated in numerous crucial cellular processes, but it is also frequently overexpressed in cancer. O-GlcNAc Transferase (OGT) governs the addition of N-acetylglucosamine residues onto cytosolic, nuclear and mitochondrial proteins. Like FASN, OGT actively participates in carcinogenesis. We previously showed that OGT regulates FASN in different ex vivo and in vivo models. Reciprocally, FASN promotes OGT expression and activity. The two enzymes physically interact together and contribute to cancer cell survival. It is therefore fundamental to define the respective interaction region of each enzyme to explore new therapeutic solutions for patients suffering from cancer. By using the hepatocarcinoma cell line Hep3B, we show thanks to two series of deletion mutants that both enzymes preferentially interact via their respective N-terminal regions. Analysis of the O-GlcNAc status of the various FASN deletion mutants shows that stronger interaction with OGT correlates with higher glycosylation, suggesting that OGT catalyzes the transfer of GlcNAc with limited substrate specificity.

Keywords: Fatty acid synthase; Liver cancer cells; N-terminal region; O-GlcNAc transferase; O-GlcNAcylation

DOI: https://doi.org/10.1016/j.bbrep.2025.102427

bioRxiv. 2025 Dec 07. pii: 2025.12.03.692150. [Epub ahead of print]

Neddylation Regulates Mitochondrial Dynamics and Turnover in the Adult Heart.

Jianqiu Zou, Wenjuan Wang, Chen Qu, Lingxian Zhang, Josue Zambrano-Carrasco, Yilang Li, Yi Lu, Hongyi Zhou, Kunzhe Dong, Tohru Fukai, Masuko Ushio-Fukai, Dawn Bowles, Michelle Mendiola Pla, Ryan Gross, Weiqin Chen, Jiliang Zhou, Jie Li, Huabo Su.

BACKGROUND: Disruption of mitochondrial homeostasis drives cardiomyopathy and heart failure, yet upstream regulatory mechanisms remain poorly defined. Neddylation, a reversible post-translational conjugation of the ubiquitin-like protein NEDD8 by E1/E2/E3 enzymes, is essential for cardiac morphogenesis, but its role in the adult heart is unknown.
METHODS: We assessed the relevance of neddylation to human cardiac disease by gene set enrichment analysis of ischemic (ICM) and non-ischemic cardiomyopathy (NICM) datasets and by immunoblotting and qPCR of ventricular tissue from patients with ICM or dilated cardiomyopathy (DCM). In adult mice, we induced cardiomyocyte-restricted deletion of the NEDD8-activating enzyme 1 (NAE1) by tamoxifen injection and monitored cardiac function at baseline and after transverse aortic constriction (TAC). Bulk RNA-seq 4 weeks post-tamoxifen was combined with bioenergetic, biochemical, and ultrastructural analyses. To assess mitochondrial dynamics, we generated NAE1/MFN2 and NAE1/DRP1 double-knockout mice. Cullin activity, mitochondrial ubiquitination, and mitophagy were measured in hearts and cultured cardiomyocytes.
RESULTS: Neddylation pathways were dysregulated in human ICM and NICM datasets and in failing ICM/DCM myocardium. Cardiomyocyte-specific NAE1 deletion caused systolic dysfunction and heart failure by 10 weeks post-tamoxifen, culminating in premature death and exacerbating TAC-induced pressure-overload heart failure. At 4 weeks, NAE1 loss repressed metabolic and mitochondrial bioenergetic programs, reduced ATP production, and impaired respiration. Electron microscopy revealed elongated mitochondria and accumulated mitophagic vesicles, with dysregulation of DRP1, MFN2, PINK1, LC3-II, and p62. DRP1/NAE1 co-deletion accelerated systolic failure relative to either single knockout, whereas MFN2/NAE1 co-deletion did not alter early disease progression, implicating pathogenic mitochondrial hyperfusion. Genetic NAE1 depletion in vivo and pharmacologic NAE1 inhibition in vitro impaired mitophagic vesicle formation and flux, inactivated cullin scaffold proteins, reduced mitochondrial ubiquitination, and blunted mitophagic clearance.
CONCLUSIONS: Cardiac neddylation preserves adult heart function by coordinating mitochondrial fusion-fission dynamics and sustaining cullin-dependent ubiquitination and turnover of damaged mitochondria. These findings identify neddylation as a key regulator of mitochondrial quality control and link its disruption to human cardiomyopathy. Therapeutically, targeting the neddylation-cullin axis may limit mitochondrial dysfunction, enhance mitophagy, and improve energetic reserve in failing hearts, while neddylation signatures in patient myocardium may help guide stratification and precision therapy for cardiomyopathy.
Clinical Perspective: What Is New?: • Demonstrates for the first time that the NEDD8-activating enzyme (NAE1)driven neddylation pathway is indispensable for maintaining mitochondrial quality control in the adult heart.• Links loss of neddylation to mitochondrial hyperfusion, impaired mitophagy, and rapid progression to heart failure.• Reveals that neddylation promotes cullin-RING ligase-mediated ubiquitination of damaged mitochondria, coupling mitochondrial dynamics with turnover.What Are the Clinical Implications?: • Restoring or enhancing cardiac neddylation may represent a novel therapeutic avenue for cardiomyopathies characterized by mitochondrial dysfunction.• Pharmacologic agents that bolster DRP1-dependent fission or activate cullin neddylation could potentially normalize mitochondrial dynamics and improve myocardial energetics.• Conversely, systemic neddylation inhibitors now in oncology trials warrant careful cardiac monitoring, as they may precipitate mitochondrial injury and heart failure.• Circulating or tissue markers of neddylation might help stratify patients at heightened risk for mitochondrial-driven cardiac disease and guide precision therapy.

DOI: https://doi.org/10.64898/2025.12.03.692150