Sulfite oxidase deficiency causes persulfidation loss and hydrogen sulfide release
Sulfite oxidase (SOX) deficiency is a rare inborn error of cysteine metabolism resulting in severe neurological damage. In patients, sulfite accumulates to toxic levels, causing a rise in the downstream products S-sulfocysteine, which mediates excitotoxicity, and thiosulfate, a catabolic intermediate/product of hydrogen sulfide (H2S) metabolism. Here, we report a full-body knockout mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Among the urinary biomarkers, thiosulfate showed a 45-fold accumulation in SOXD mice, representing the major excreted S-metabolite. Consistently, we found increased plasma H2S, which was derived from sulfite-induced release from persulfides, as demonstrated in vitro and in vivo. Mass spectrometry analysis of total protein persulfidome identified a major loss of S-persulfidation in 20% of the proteome, affecting enzymes in amino acids, fatty acid metabolism, and cytosolic iron-sulfur cluster biogenesis. Urinary amino acid profiles indicated metabolic rewiring and mitochondrial dysfunction, thus identifying an altered H2S metabolism and persulfidation in SOXD. Finally, oxidized glutathione and glutathione trisulfide were able to scavenge sulfite in vitro and in vivo, extending the lifespan of SOXD mice and providing a mechanistic concept of sulfite scavenging for the treatment of this severe metabolic disorder of cysteine catabolism.
Authors
- Uladzimir Barayeu (ORCID: https://orcid.org/0000-0001-8426-166X)
- Seiryo Ogata (ORCID: https://orcid.org/0000-0001-5422-7823)
- Davide D’Andrea
- Takaaki Akaike
- Franziska Neuser
- Michaela Křížková
- José Angel Santamaria‐Araujo
- Miloš R. Filipović (ORCID: https://orcid.org/0000-0003-0060-0041)
- Joshua B. Kohl (ORCID: https://orcid.org/0000-0002-3461-089X)
- Sin Yuin Yeo (ORCID: https://orcid.org/0000-0002-7602-0695)
- Heike Endepols (ORCID: https://orcid.org/0000-0002-6166-4818)
- Tamás Ditrói
- Emilia Kouroussis
- Masanobu Morita (ORCID: https://orcid.org/0000-0002-5259-5371)
- Péter Nagy (ORCID: https://orcid.org/0000-0003-3393-235X)
- Julia B. Hennermann (ORCID: https://orcid.org/0000-0003-2639-1233)
- Chun-Yu Fu (ORCID: https://orcid.org/0000-0002-5382-528X)
- Viktor Kožich (ORCID: https://orcid.org/0000-0001-5820-5277)
- Filip Liebsch (ORCID: https://orcid.org/0000-0002-0955-8065)
- Günter Schwarz (ORCID: https://orcid.org/0000-0002-2118-9338)
- Titus Gehling (ORCID: https://orcid.org/0000-0001-5004-5061)
- Max Mai
- Anna T. Mellis
- Marcus Krueger
Institutions
- University of Debrecen (HU)
- Forschungszentrum Jülich (DE)
- University of Cologne (DE)
- Johannes Gutenberg University Mainz (DE)
- Tohoku University (JP)
- Charles University (CZ)
- Society of Interventional Radiology (US)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Max Planck Institute for Polymer Research (DE)
- HUN-REN Institute of Experimental Medicine (HU)
- National Institute of Oncology (HU)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- General University Hospital in Prague (CZ)
- Hungarian Academy of Sciences (HU)
- University of Glasgow (GB)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-11-02
- DOI
- https://doi.org/10.1172/jci181299
- Citations
- 3
- Primary Topic
- Sulfur Compounds in Biology
- Type
- article
- Field-Weighted Citation Impact
- 3.34
Funders
- Univerzita Karlova v Praze
- European Commission
- Deutsche Forschungsgemeinschaft
- Agentura Pro Zdravotnický Výzkum České Republiky
- Všeobecná Fakultní Nemocnice v Praze
- Nemzeti Kutatási, Fejlesztési és Innovaciós Alap
- National Research, Development and Innovation Office