TY  - JOUR
AU  - Fu, Chun-Yu
AU  - Kohl, Joshua B.
AU  - Liebsch, Filip
AU  - D’Andrea, Davide
AU  - Ditrói, Tamás
AU  - Ogata, Seiryo
AU  - Neuser, Franziska
AU  - Mai, Max
AU  - Mellis, Anna T.
AU  - Kouroussis, Emilia
AU  - Morita, Masanobu
AU  - Gehling, Titus
AU  - Santamaria-Araujo, José Angel
AU  - Yeo, Sin Yuin
AU  - Endepols, Heike
AU  - Křížková, Michaela
AU  - Kozich, Viktor
AU  - Krueger, Marcus
AU  - Hennermann, Julia B.
AU  - Barayeu, Uladzimir
AU  - Akaike, Takaaki
AU  - Nagy, Peter
AU  - Filipovic, Milos
AU  - Schwarz, Guenter
TI  - Sulfite oxidase deficiency causes persulfidation loss and hydrogen sulfide release
JO  - The journal of clinical investigation
VL  - 135
IS  - 21
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - FZJ-2025-04520
SP  - e181299
PY  - 2025
AB  - 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.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1172/JCI181299
UR  - https://juser.fz-juelich.de/record/1048140
ER  -