Sulfite oxidase deficiency causes persulfidation loss and H2S release

Fu, C.-Y.; Kohl, J. B.; Liebsch, F.; D`Andrea, D.; Mai, M.; Mellis, A. T.; Kouroussis, E.; Ditroi, T.; Santamaria-Araujo, J. A.; Yeo, S. Y.; Endepols, H.; Krizkov, M.; Kozich, V.; Barayeu, U.; Akaike, T.; Hennermann, J. B.; Nagy, P.; Filipovic, M.; Schwarz, G.

doi:10.1101/2024.03.13.584820

bioRxiv · 10.1101/2024.03.13.584820

Sulfite oxidase deficiency causes persulfidation loss and H2S release

Fu, C.-Y.·Kohl, J. B.·Liebsch, F.·D`Andrea, D.·Mai, M.·Mellis, A. T.·Kouroussis, E.·Ditroi, T.·Santamaria-Araujo, J. A.·Yeo, S. Y.·Endepols, H.·Krizkov, M.·Kozich, V.·Barayeu, U.·Akaike, T.·Hennermann, J. B.·Nagy, P.·Filipovic, M.·Schwarz, G.

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Abstract

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 raise in downstream products S-sulfocysteine (SSC), mediating excitotoxicity, and thiosulfate, a catabolic intermediate/product of H2S metabolism. Here, we report a full-body knock-out mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Amongst 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 spectrometric analysis of total protein persulfidome identified a major loss of persulfidation in 20% of the proteome affecting enzymes in amino acids and fatty acid metabolism. Urinary amino acid profiles indicate metabolic rewiring suggesting partial reversal of the TCA cycle thus identifying a novel contribution of H2S metabolism and persulfidation in SOXD.

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Fu, C.-Y., Kohl, J. B., Liebsch, F., D`Andrea, D., Mai, M., Mellis, A. T., Kouroussis, E., Ditroi, T., Santamaria-Araujo, J. A., Yeo, S. Y., Endepols, H., Krizkov, M., Kozich, V., Barayeu, U., Akaike, T., Hennermann, J. B., Nagy, P., Filipovic, M., Schwarz, G.. 2024-03-13. Sulfite oxidase deficiency causes persulfidation loss and H2S release. https://doi.org/10.1101/2024.03.13.584820

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