Dataset Information

Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction

ABSTRACT: Purpose: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare mitochondrial encephalomyopathy subtype, is caused by mutations of thymidine phosphorylase (TYMP). As a metabolic enzyme localized in the cytoplasm, the biological processes disturbed by TYMP functional defect are supposed to be not limited in the abnormal replication of mitochondrial DNA. This study aimed to elucidate the characteristic biological alterations and associated homeostatic regulation caused by TYMP deficiency. Methods: Clinical evaluation and genetic analysis were performed on three patients from two independent families carrying heterozygous TYMP variants. Molecular dynamic (MD) simulation and nucleosides detection were used to investigate the pathogenicity of the variants. Plasma from patients with MNGIE and m.A3243G MELAS and healthy volunteers were analyzed by targeted and untargeted metabolomics to characterize the metabolic profiles of MNGIE. Transcriptomics analysis and bioenergetic studies were performed on skin fibroblasts from these three groups of subjects. Results: Three novel TYMP pathogenic variants were identified in our MNGIE patients. Total 72 plasma metabolites were identified as specific alterations of MNGIE patients through comparing the differentially changed metabolites in MNGIE patients and m.A3243G MELAS patients. Beside pyrimidine metabolism, MNGIE patients showed significant changes in multiple metabolisms, such as bile acids metabolism, caffeine metabolism and steroid hormone metabolism. Despite comparable mitochondrial dysfunction existing in fibroblasts from patients with TYMP deficiency and ones with m.A3243G mutation, a distinct downregulated cholesterol metabolism and fatty acids (FAs) metabolism were revealed in the fibroblasts from MNGIE patients via multiple analysis of metabolites levels, metabolic enzymes expression, mitochondrial substrates dependency and transcription factors expression. Conclusions: Our findings revealed a more expansive metabolic disturbance may be caused by TYMP deficiency beyond mitochondrial disfunction, extending a comprehensive understanding of the biochemical outcome of TYMP deficiency.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222921 | GEO | 2025/03/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background: The heteroplasmic mitochondrial DNA (mtDNA) mutation A3243G causes the MELAS syndrome as one of the most frequent mitochondrial diseases. The process of reconfiguration of nuclear gene expression profile to accommodate cellular processes to the functional status of mitochondria might be a key to MELAS disease manifestation and could contribute to its diverse phenotypic presentation. Objective: To determine master regulatory protein networks and disease-modifying genes in MELAS syndrome. Methods: Analyses of whole blood transcriptomes from 10 MELAS patients using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses. Results and Interpretation: Hierarchical cluster analysis elucidated that the relative abundance of mutant mtDNA molecules is decisive for the nuclear gene expression response. Further analyses confirmed not only transcription factors already known to be involved in mitochondrial diseases (such as TFAM), but also detected the hypoxia-inducible factor 1α (HIF-1α)/HIF-1β complex, nuclear factor Y (NF-Y) and CREB-related transcription factors as novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation. Correlation analyses of gene alterations and clinico-genetic data detected significant correlations between A3243G-induced nuclear gene expression changes and mutant mtDNA load as well as disease characteristics. These potential disease-modifying genes influencing the expression of the MELAS phenotype are mainly related to clusters primarily unrelated to cellular energy metabolism, but important for nucleic acid and protein metabolism, and signal transduction. Our data thus provide a framework to search for new pathogenetic concepts and potential therapeutic approaches to treat the MELAS syndrome. Peripheral blood samples were collected from ten A3243G MELAS patients and twenty age- and sex-matched healthy controls (2 controls for each patient). The patient cohort consisted of 4 females and 6 males, mean±s.e.m. age was 44.1±11.9 years (range: 22–63 years), mean±s.e.m. age at disease onset was 27.1±4.9 years (range: 13–55 years), mean±s.e.m. disease duration was 19.0±4.7 years (range: 4–43 years), and disease severity measured by the ‘Newcastle Mitochondrial Disease Adult Scale’ (NMDAS) 8 ranging from 0.0 (no symptoms) to 1.0 (maximum score) was 0.26±0.05 (range: 0.02–0.54).

Dataset Information

Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets