Deciphering pathophysiological mechanisms underlying cystathionine beta-synthase-deficient homocystinuria using targeted metabolomics, liver proteomics, sphingolipidomics and analysis of mitochondrial function
DOKPE
- Majtan, Tomas ORCID University of Fribourg
- Olsen, Thomas ORCID University of Oslo, Norway
- Sokolova, Jitka ORCID Charles University, Prague, Czech Republic
- Krijt, Jakub ORCID Charles University, Prague, Czech Republic
- Křížková, Michaela Charles University, Prague, Czech Republic
- Ida, Tomoaki Tohoku University, Sendai, Japan
- Ditrói, Tamás National Institute of Oncology, Budapest, Hungary
- Hansikova, Hana Charles University, Prague, Czech Republic
- Vit, Ondrej ORCID Charles University, Vestec, Czech Republic
- Petrak, Jiri ORCID Charles University, Vestec, Czech Republic
- Kuchař, Ladislav ORCID Charles University, Prague, Czech Republic
- Kruger, Warren D. ORCID Fox Chase Cancer Center, Philadelphia, PA, USA
- Nagy, Péter National Institute of Oncology, Budapest, Hungary
- Akaike, Takaaki Tohoku University, Sendai, Japan
- Kožich, Viktor ORCID Department of Pediatrics and Inherited Metabolic Disorders, Charles University-First Faculty of Medicine, Prague, 12808, Czech Republic
- 2024
Published in:
- Redox Biology. - US : Elsevier BV. - 2024, vol. 73, p. 103222
English
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 imbalance 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 sphingolipidomics indicated upregulation of the pro-proliferative 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 metabolome, proteome and sphingolipidome disruptions in I278T mice, and the efficacy of MRD to alleviate some of the HCU-related biochemical abnormalities.
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 imbalance 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 sphingolipidomics indicated upregulation of the pro-proliferative 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 metabolome, proteome and sphingolipidome disruptions in I278T mice, and the efficacy of MRD to alleviate some of the HCU-related biochemical abnormalities.
- Faculty
- Faculté des sciences et de médecine
- Department
- Médecine 3ème année
- Language
-
- English
- Classification
- Pharmacology, therapeutics, toxicology
- License
- CC BY
- Open access status
- hybrid
- Identifiers
-
- DOI 10.1016/j.redox.2024.103222
- ISSN 2213-2317
- Persistent URL
- https://folia.unifr.ch/unifr/documents/328933
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