Impaired mitochondrial maturation of sulfite oxidase in a patient with severe sulfite oxidase deficiency

Abstract

Sulfite oxidase (SO) is encoded by the nuclear SUOX gene and catalyzes the final step in cysteine catabolism thereby oxidizing sulfite to sulfate. Oxidation of sulfite is dependent on two cofactors within SO, a heme and the molybdenum cofactor (Moco), the latter forming the catalytic site of sulfite oxidation. SO localizes to the intermembrane space of mitochondria where both—pre-SO processing and cofactor insertion—are essential steps during SO maturation. Isolated SO deficiency (iSOD) is a rare inborn error of metabolism caused by mutations in the SUOX gene that lead to non-functional SO. ISOD is characterized by rapidly progressive neurodegeneration and death in early infancy. We diagnosed an iSOD patient with homozygous mutation of SUOX at c.1084G>A replacing Gly362 to serine. To understand the mechanism of disease, we expressed patient-derived G362S SO in Escherichia coli and surprisingly found full catalytic activity, while in patient fibroblasts no SO activity was detected, suggesting differences between bacterial and human expression. Moco reconstitution of apo-G362S SO was found to be approximately 90-fold reduced in comparison to apo-WT SO in vitro. In line, levels of SO-bound Moco in cells overexpressing G362S SO were significantly reduced compared to cells expressing WT SO providing evidence for compromised maturation of G362S SO in cellulo. Addition of molybdate to culture medium partially rescued impaired Moco binding of G362S SO and restored SO activity in patient fibroblasts. Thus, this study demonstrates the importance of the orchestrated maturation of SO and provides a first case of Moco-responsive iSOD.

Severe isolated sulfide oxidase deficiency with a novel mutation

“…Other laboratory findings include increased thiosulfate in urine, increased S-sulfocysteine and taurine in plasma and urine; normal plasma methionine, lowered plasma cysteine and homocysteine in ISOD. [1][2][3][4] Our patient's amino acid analysis including homocysteine was found to be normal.…”

“…1 Eighteen different mutations in SUOX gene have been described in about 50 patients to date. [1][2][3][4] Most of the patients reported had severe neurological findings, mainly related with sulfite toxicity, presenting in the neonatal period. The severity of the disease depends on the mutation and associated residual enzyme activity.…”

Case Report: Compound Heterozygous Variants in MOCS3 Identified in a Chinese Infant With Molybdenum Cofactor Deficiency

“…Accumulation of S-sulphocysteine and thiosulfate would activate the N-methyl-D-aspartate receptor and increase intracellular magnesium and calcium. This could enhance the permeability of the mitochondria, compromise the mitochondrial energy supply, and reduce the cell viability in cerebral cortex of rat brain (Grings et al, 2014;Marelja et al, 2018;Bender et al, 2019;Plate et al, 2019). All these processes may be the possible mechanisms underlying the neurological dysfunction observed in our patient.…”

“…However, Moco deficiency usually presents more aggressive neurological symptoms. The positive urine test for sulfite with decreased plasma and urine uric acid would assist diagnosis (Yoganathan et al, 2018;Bender et al, 2019).…”

Impacts ofDesulfobacteralesandChromatialeson sulfate reduction in the subtropical mangrove ecosystem as revealed by SMDB analysis

“…Notably, sulfite is cytotoxic above a certain threshold if not rapidly metabolized and can wreak havoc at the cellular and whole-plant levels. By providing the gene families of asrC, asrA, asrB, cysI, cysJ, and cysH that reduces sulfite levels to protect the members of the local community (Bender et al, 2019;Hensel et al, 1999). If sulfite reductase is absent, most organisms in the community would be inhibited and grow slowly.…”