Gaucher disease linked to changes in cell energy and fat processing
Modeling study points to mitochondrial and cholesterol shifts
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Gaucher disease may alter how macrophages, key immune cells involved in the disease, produce energy and process fats, according to a new study using computational modeling.
Based on their model, researchers identified a few genes that may help regulate these metabolic changes in Gaucher cells. The scientists called for further investigation into whether these genes could serve as potential biomarkers or treatment targets.
Study uses computer models to examine Gaucher cells
An early-access version of the study, “Constraint-based modelling of metabolic dysregulation in Gaucher disease: mitochondrial dysfunction and disrupted cholesterol homeostasis,” was published in the Orphanet Journal of Rare Diseases.Â
Macrophages are immune cells that act like the body’s trash collectors, gathering up molecular debris and disposing of it. When macrophages encounter cellular waste, they engulf it and deliver it to a cellular compartment called the lysosome, which acts as a molecular garbage disposal, breaking down large molecules into simpler components that can be reused by the cell.
Gaucher disease is caused by mutations that interfere with the function or production of an enzyme called glucocerebrosidase (GCase), which is needed to break down certain fatty molecules in the lysosome.
In the absence of a functional GCase, lysosomes cannot properly break down these fatty molecules. As a result, they accumulate within lysosomes, ultimately causing cellular dysfunction that drives Gaucher symptoms.
It is well recognized that Gaucher disease affects lysosomes in macrophages, but other parts of these immune cells may also be disrupted. Still, the details are not fully understood because current experimental models do not fully capture how these cells behave in the disease.
Models predict shifts in how cells generate energy
To better understand how Gaucher disease affects macrophages, a team of scientists in Ireland turned to computer models. They integrated genomic and metabolic data, along with information curated from the scientific literature, to construct computer-based models of macrophage activity in people with and without Gaucher disease.
“Computational modelling [provides] a systematic, mechanistic representation of human cellular metabolism. Genome-scale metabolic models integrate curated biochemical knowledge into a comprehensive network of metabolic reactions,” the researchers wrote.
The models predicted that, in Gaucher disease, macrophages broadly shift how they generate energy. Normally, macrophages and most other cells produce much of their energy using a process in the mitochondria called oxidative phosphorylation. This process is relatively slow, but it is very efficient.
Notably, oxidative phosphorylation relies on cellular structures called mitochondria — which is why these organelles are often called the “powerhouse of the cell.”
The models suggested that Gaucher macrophages have reduced mitochondrial activity, meaning they may rely less on oxidative phosphorylation. Instead, the models indicated that these cells may shift toward a faster but less efficient process called glycolysis to meet their energy needs.
“Our model-based predictions indicate a pronounced shift in energy metabolism in [Gaucher disease] models under increasing energy demand, characterised by diminished reliance on oxidative phosphorylation and a compensatory upregulation of glycolysis,” the scientists wrote, noting that these computer-based analyses are consistent with prior studies in cell models that suggested Gaucher disease can cause problems with mitochondria.
Key genes emerge as possible metabolic regulators
The model also indicated that Gaucher macrophages may change the way they process many different types of fatty molecules, not just the specific molecules that are broken down by the GCase enzyme. This likely reflects the cell’s attempt to compensate for the buildup of fatty molecules that cannot be broken down, the researchers said.
The model also suggested that a few key genes may be important for regulating these shifts in metabolic activity within Gaucher macrophages. Two specific genes involved in the process, called ASAH1 and CPT1A, were identified through computational analysis as candidate modifier genes and may offer useful biomarkers or targets for treatments, but more research will be needed to confirm this.
“The identification of ASAH1 and CPT1A as candidate disease modifiers highlights metabolic nodes that could influence disease progression or therapeutic response,” the researchers concluded. “Overall, the modelling framework generates mechanistically grounded predictions and provides a basis for developing biomarkers and intervention strategies that can be evaluated experimentally.”
