Dataset Information

Multiomics approach to decipher pathophysiological mechanisms and therapeutic impact of methionine restriction in cystathionine β-synthase deficient homocystinuria

ABSTRACT: Background. Cystathionine β-synthase (CBS)-deficient homocystinuria (HCU) is an inherited disorder of sulfur amino acid metabolism with varying severity and organ complications, and a limited knowledge about underlying pathophysiological processes. Here we aimed at getting an in-depth insight into disease mechanisms using a transgenic mouse model of HCU (I278T). Methods. We assessed metabolic, proteomic and sphingolipidomic changes, and mitochondrial function in tissues and body fluids of I278T mice and WT controls. Furthermore, we evaluated the efficacy of methionine-restricted diet (MRD) in I278T mice. Results. In WT mice, we observed a distinct tissue/body fluid compartmentalization of metabolites with up to six-orders of magnitude differences in concentrations among various organs. The I278T mice exhibited the anticipated metabolic disbalance with signs of an increased production of hydrogen sulfide and disturbed persulfidation of free aminothiols. HCU resulted in a significant dysregulation of liver proteome affecting biological oxidations, conjugation of compounds, and metabolism of amino acids, vitamins, cofactors and lipids. Liver phospholipidomics indicated upregulation of the pro-proliferative sphingomyelin-ceramide-sphingosine-1-phosphate signaling pathway. Liver mitochondrial function of HCU mice did not seem to be impaired compared to controls. MRD in I278T mice improved metabolic balance in all tissues and substantially reduced dysregulation of liver proteome. Conclusion. The study highlights distinct tissue compartmentalization of sulfur-related metabolites in normal mice, extensive metabolic, proteomic and sphingolipidomic disruptions in I278T mice, and the efficacy of MRD to alleviate some of the HCU-related biochemical abnormalities.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Ondrej Vit

LAB HEAD: Jiri Petrak

PROVIDER: PXD049417 | Pride | 2024-07-03

REPOSITORIES: Pride

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Deciphering pathophysiological mechanisms underlying cystathionine beta-synthase-deficient homocystinuria using targeted metabolomics, liver proteomics, sphingolipidomics and analysis of mitochondrial function.

Majtan Tomas T Olsen Thomas T Sokolova Jitka J Krijt Jakub J Křížková Michaela M Ida Tomoaki T Ditrói Tamás T Hansikova Hana H Vit Ondrej O Petrak Jiri J Kuchař Ladislav L Kruger Warren D WD Nagy Péter P Akaike Takaaki T Kožich Viktor V

Redox biology 20240604

<h4>Background</h4>Cystathionine β-synthase (CBS)-deficient homocystinuria (HCU) is an inherited disorder of sulfur amino acid metabolism with varying severity and organ complications, and a limited knowledge about underlying pathophysiological processes. Here we aimed at getting an in-depth insight into disease mechanisms using a transgenic mouse model of HCU (I278T).<h4>Methods</h4>We assessed metabolic, proteomic and sphingolipidomic changes, and mitochondrial function in tissues and body flu ...[more]

PMID: 38843767

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