Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction

This study aimed to elucidate the characteristic metabolic alterations and associated homeostatic regulation caused by TYMP deficiency. The pathogenicity of novel TYMP variants was evaluated in terms of clinical features, genetic analysis, and structural instability. We analyzed plasma samples from three patients with MNGIE; three patients with m.3243A  >  G mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); and four healthy controls (HC) using both targeted and untargeted metabolomics techniques. Transcriptomics analysis and bioenergetic studies were performed on skin fibroblasts from participants in these three group s. A TYMP overexpression experiment was conducted to rescue the observed changes. Compared with controls, specific alterations in nucleosides, bile acids, and steroid metabolites were identified in the plasma of MNGIE patients. Comparable mitochondrial dysfunction was present in fibroblasts from pat ients with TYMP deficiency and in those from patients with the m.3243A >  G mutation. Distinctively decreased sterol regulatory element binding protein (SREBP) regulated cholesterol metabolism and fatty acid (FA) biosynthesis as well as reduced FA degradation were revealed in fibroblasts with TYMP deficiency. The restoration of thymidine phosphorylase activity rescued the observed changes in MNGIE fibroblasts. Our findings indicated that more widespread metabolic disturbance may be caused by TYMP deficiency in addition to ...
Source: Journal of Molecular Medicine - Category: Molecular Biology Source Type: research