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Sulfite oxidase-deficient mice disclose a novel contribution of hydrogen sulfide to the pathomechanism of sulfite toxicity

ABSTRACT: Sulfite oxidase (SOX) deficiency is a rare inborn error in metabolism resulting in severe neurological damage. As terminal intermediate of cysteine cataboilism, sulfite accumulats to toxic levels causing a raise in downstream products such as S-sulfocysteine (SSC), mediating excitotoxic action, and thiosulfate, a catabolic end product of H2S metabolism. SOX is a molybdenum cofactor dependent enzyme and patients with defects in the biogenesis of Moco exhibit similar symptoms as patients with SOX deficiency. Here, we generated a first full-body knock-out mouse model for isolated SOX deficiency (iSOD). Homozygous SuoxKO/KO mice were severely impaired with an average lifespan of 9.6 days. Surprisingly, they show no neuropathological phenotype as observed in human patients. Biomarkers such as sulfite and SSC were only moderately increased in urine, while thiosulfate showed strongest, 45-fold accumulation in urine of SuoxKO/KO mice. To our surprise, the metabolic precursor of thiosulfate, H2S was only two-fold increae in plasma being consistent with no major change in H2S metabolism. As primary source of the massive thiosulfate excretion we identified a loss in a global protein persulfidation due to sulfite accumulation in SuoxKO/KO mice liver extracts resulting in the liberation of H2S. Mass spectrometric analysis of the global protein persulfidome identified a major loss of S-persulfidation in enzymes involved in amino acids and fatty acid metabolism. In aggregate our study identified a noivel contribution of H2S metabolism and persulfidation in the pathomechanism of iSOD, which also applies to patients suffering from molybdenum cofactor deficiency. Using chemoproteomic approaches, we assessed persulfidation levels in WT and SUOX-/- mice liver. To ensure that persulfidation changes were not due to the protein expression changes, we also measured the total proteome in the same samples.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Davide D´Andrea

LAB HEAD: Milos Filipovic

PROVIDER: PXD045896 | Pride | 2025-10-13

REPOSITORIES: Pride

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			Action	DRS
	Eclipse_03573_MM_liver_FP_WT1.raw	Raw
	Eclipse_03573_MM_liver_FP_WT1.raw.mzxml	Mzxml
	Eclipse_03573_MM_liver_FP_WT1.raw.refined.mgf	Mgf
	Eclipse_03574_MM_liver_FP_KO1.raw	Raw
	Eclipse_03574_MM_liver_FP_KO1.raw.mzxml	Mzxml

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Project description:Persulfidation, a posttranslational modification of cysteines to persulfides, is the best characterized molecular mechanism of H2S signaling. This study is focused on new functions for thioredoxins (TRXs) in plants beyond those of thiol disulfide (S-S) exchange, including the regulation of protein persulfidation as it has been described in animal systems. To elucidate the impact of TRXo1 deficiency on the protein persulfidation pattern in plants of Arabidopsis thaliana L. wild-type (WT) and two Attrxo1 T-DNA insertion mutants grown under non stress conditions, a quantitative proteomic approach was performed. The proteomic analysis revealed a higher number of proteins that were more persulfidated in the mutants compared to WT plants, suggesting a role for TRXo1 in protein depersulfidation. Interestingly, most of the differentially persulfidated proteins were located in the chloroplast, implying a coordination between chloroplast H2S-dependent persulfidation and mitochondrial TRXo1 depersulfidation. Among the differentially persulfidated proteins located in mitochondria, the antioxidant enzymes sAPX, DHAR1, and MDAR6 were selected for further studies. The effect of H2S-dependent persulfidation on their enzymatic activities and its reversibility by the NADPH/thioredoxin reductase (NTRB)/TRXo1 system was analyzed, as well as their persulfidation levels were quantified. Sulfide treatment brought about increases in the activity levels of the enzymes, that match with a raise on the persulfidation levels. Interestingly, both activations declining after treatment with the thioredoxin system, indicating regulation of their persulfidation by TRXo1. These results point to a positive effect of persulfidation on the enzymatic activities and also to a new depersulfidase activity for TRXo1. All together these results give a new insight of the mechanism of elimination of -SSH groups in plants exerted by TRXo1, and the involvement of a redox regulation on the protein persulfidation.

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Sulfite oxidase-deficient mice disclose a novel contribution of hydrogen sulfide to the pathomechanism of sulfite toxicity

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