# Constraint-based modelling of metabolic dysregulation in Gaucher disease: mitochondrial dysfunction and disrupted cholesterol homeostasis

## TL;DR

This study uses metabolic modeling to uncover how Gaucher disease disrupts mitochondrial and cholesterol metabolism in macrophages.

## Contribution

A constraint-based metabolic modeling framework was developed to identify systemic metabolic changes in Gaucher disease macrophages.

## Key findings

- GD macrophages shift from oxidative phosphorylation to glycolysis due to mitochondrial dysfunction.
- Cholesterol biosynthesis is upregulated intracellularly despite low systemic cholesterol in GD.
- ASAH1 and CPT1A are predicted as key modifier genes affecting lipid and mitochondrial metabolism.

## Abstract

Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in the GBA1 gene, leading to deficient glucocerebrosidase activity and accumulation of glucosylceramide in macrophages. Beyond lysosomal dysfunction, GD is associated with widespread metabolic abnormalities, yet the molecular basis of these changes remains incompletely understood. This study employed constraint-based genome-scale metabolic modelling to investigate systemic metabolic reprogramming in GD macrophages, aiming to uncover disrupted pathways and mechanistic drivers of disease phenotypes.

A total of 150 pairs of high-quality macrophage-specific models under Gaucher and control conditions were developed using a semi-automated pipeline to integrate transcriptomic, exometabolomic and bibliomic data. These Gaucher models captured disease-specific perturbations by incorporating gene expression profiles from GD macrophages. Simulations predicted a shift from oxidative phosphorylation to glycolysis under energy stress in GD, attributed to impaired mitochondrial ATP transport and reduced activity of respiratory complexes. Lipid metabolism was profoundly altered, with increased de novo ceramide synthesis, defective ganglioside processing, and dysregulated cholesterol metabolism. Despite clinically observed hypocholesterolaemia, the models predicted upregulated intracellular cholesterol biosynthesis, suggesting a disconnect between intracellular and systemic cholesterol pools. Reporter metabolite analysis further highlighted cholesterol, sphingolipids, and acylcarnitine as hubs of transcriptional dysregulation. Robust metabolic transformation analysis predicted ASAH1(acid ceramidase) and CPT1A (carnitine palmitoyl transferase 1 A) as potential modifier genes influencing lipid catabolism and mitochondrial function. Several model predictions were corroborated by independent experimental findings, supporting their biological plausibility.

This study demonstrates the utility of constraint-based metabolic modelling in elucidating the systems-level metabolic dysfunction underlying GD. The results highlight a core axis of mitochondrial and lipid metabolic disruption, particularly involving cholesterol homeostasis, as a central feature of disease pathophysiology. These predictions provide mechanistic insight into the cellular consequences of lysosomal dysfunction and identify candidate metabolic biomarkers and therapeutic targets. The modelling framework developed here supports hypothesis generation and future applications in precision medicine for lysosomal storage disorders.

The online version contains supplementary material available at 10.1186/s13023-026-04206-8.