Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction.

Area of Science:

• Biochemistry
• Genetics
• Metabolomics

Background:

• Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a genetic disorder linked to thymidine phosphorylase (TP) deficiency.
• TP is a cytosolic enzyme, suggesting its role extends beyond mitochondrial DNA replication.
• Understanding the full metabolic impact of TYMP deficiency is crucial for MNGIE.

Purpose of the Study:

• To identify metabolic alterations and regulatory mechanisms in TYMP deficiency.
• To evaluate the pathogenicity of novel TYMP variants.
• To compare metabolic profiles of MNGIE patients with MELAS patients and healthy controls.

Main Methods:

• Analysis of plasma samples from MNGIE patients, MELAS patients, and healthy controls using metabolomics.
• Transcriptomics and bioenergetic studies on skin fibroblasts.
• TYMP overexpression experiments to assess functional rescue.

Main Results:

• MNGIE patients exhibited distinct alterations in plasma nucleosides, bile acids, and steroid metabolites.
• Fibroblasts from TYMP-deficient patients showed mitochondrial dysfunction, similar to MELAS patients.
• TYMP deficiency led to reduced cholesterol and fatty acid metabolism, linked to SREBP pathways.

Conclusions:

• TYMP deficiency causes widespread metabolic disturbances, including nucleoside, cholesterol, and fatty acid metabolism.
• Mitochondrial dysfunction is present but not the sole consequence of TYMP deficiency.
• Metabolite biomarkers may aid in MNGIE diagnosis.