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.

Center for Molecular Medicine Cologne University of Cologne Cologne Germany

Center for Pediatric and Adolescent Medicine University Medical Center Mainz Mainz Germany

Chemistry Institute University of Debrecen Debrecen Hungary

Department of Anatomy and Histology Hungarian Research Network UVMB Laboratory of Redox Biology Research Group University of Veterinary Medicine Budapest Hungary

Department of Environmental Medicine and Molecular Toxicology Tohoku University Graduate School of Medicine Sendai Japan

Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory National Institute of Oncology Budapest Hungary

Department of Nuclear Medicine University of Cologne Faculty of Medicine and University Hospital Cologne Cologne Germany

Department of Pediatrics and Inherited Metabolic Disorders Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Forschungszentrum Jülich GmbH Institute of Neuroscience and Medicine Nuclear Chemistry Jülich Germany

Institute of Biochemistry Department of Chemistry and Biochemistry University of Cologne Cologne Germany

Institute of Diagnostic and Interventional Radiology

Institute of Genetics Department of Biology and CECAD University of Cologne Cologne Germany

Institute of Radiochemistry and Experimental Molecular Imaging and

Leibniz Institute for Analytical Sciences ISAS e 5 Dortmund Germany

Max Planck Institute for Polymer Research Mainz Germany

School of Molecular Biosciences University of Glasgow Glasgow United Kingdom

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