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B08 | Sulfite- and nitrite-dependent regulation of mitochondrial function by sulfite oxidase

Günter Schwarz
Institute for Biochemistry
University of Cologne 

E-mail: gschwarzSpamProtectionuni-koeln.de
Phone: +49 - 221 / 470 6441
For more information and contact please visit the SCHWARZ LAB.

Running time within the CRC 1218: 07/2016 - 06/2024.


Sulfite oxidase (SOX) is a molybdenum enzyme in the intermembrane space of mitochondria, which catalyses the terminal step in oxidative cysteine catabolism. A loss in SOX function results in severe neurodegeneration, due to cytotoxicity of accumulating sulfite, S-sulfocysteine and H2S leading to mitochondrial dysfunction. Here, we aim to understand the molecular mechanism of sulfite-mediated redox changes and H2S release as well as S-sulfocysteine-induced calcium influx on mitochondrial functions in SOX deficiency. Furthermore, we will investigate the mitochondrial function of SOX in nitrite-dependent NO-synthesis.

Project-related publications

Kožich, V, Schwahn, B.C., Sokolová, J., Křížková, M., Ditroi, T., Krijt, J., Khalil, Y., Křížek, T., Vaculíková-Fantlová, T., Stibůrková, B., Mills, P., Clayton, P., Barvíková, K., Blessing, H., Sykut-Cegielska, J., Dionisi-Vici, C., Gasperini, S., García-Cazorla, Á., Haack, T.B., Honzík, T., Ješina, P., Kuster, A., Laugwitz, L., Martinelli, D., Porta, F., Santer, R., Schwarz, G., Nagy, P. (2022). Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H2S homeostasis. Redox Biol. 2022 Dec;58:102517. doi: 10.1016/j.redox.2022.102517. Epub 2022 Oct 18.PMID: 36306676. Free PMC article.

Salscheider, S.L., Gerlich, S., Cabrera-Orefice, A., Peker, E., Rothemann, R.A., Murschall, L.M., Finger, Y., Szczepanowska, K., Ahmadi, Z. A., Guerrero-Castillo, S. Erdogan, A., Becker, M. Ali, M., Habich, M., Petrungaro, C., Burdina, N., Schwarz, G., Klußmann, M., Neundorf, I., Stroud, D.A., Ryan, M.T., Trifunovic, A., Brandt, U., and Riemer, J. (2022). AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5. EMBO Journal, 41, e110784.

Kaczmarek, A.T., Bender, D., Gehling, T., Kohl, J.B., Daimagüler, H.S., Santamaria-Araujo, J.A., Liebau, M.C., Koy, A., Cirak, S., Schwarz, G.J. (2021). A defect in molybdenum cofactor binding causes an attenuated form of sulfiteoxidase deficiency. Inherit Metab Dis. 2022 Mar;45(2):169-182. Do i: 10.1002/jimd.12454. Epub 2021 Nov 24.PMID: 34741542

Kaczmarek, A.T., Bahlmann, N., Thaqi, B., May, P., Schwarz, G. (2021). Machine learning-based identification and characterization of 15 novel pathogenic SUOX missense mutations. 2021 Sep-Oct;134(1-2):188-194. doi: 10.1016/j.ymgme.2021.07.011. Epub 2021 Aug 8.PMID: 34420858

Mellis, A.-T., Roepe,r J., Misko, A.L., Kohl, J., Schwarz, G. (2021). Sulfite Alters the Mitochondrial Network in Molybdenum Cofactor Deficiency.  doi: 10.3389/fgene.2020.594828.

Mellis, A.-T., Misko, A.L., Arjune, S., Liang, Y., Erdélyi, K., Ditrói, T., Kaczmarek, A. T., Nagy, P., Schwarz, G. (2021).
The role of glutamate oxaloacetate transaminases in sulfite biosynthesis and H 2 S metabolism. Redox Biol. 2021 Jan;38:101800. doi: 10.1016/j.redox.2020.101800.

Bender, D., Kaczmarek, A.T., Kuester, S., Burlina, A.B., and Schwarz G. (2020). Oxygen and nitrite reduction by heme-deficient sulphite oxidase in a patient with mild sulphite oxidase deficiency. J. Inherit. Metab. Dis. Jan 17; doi: 10.1002/jimd.12216.

Mayr, S.J., Röper, J., and Schwarz, G. (2020). Alternative splicing of the bicistronic gene molybdenum cofactor synthesis 1 (MOCS1) uncovers a novel mitochondrial protein maturation mechanism. J. Biol. Chem., Jan 29. pii: jbc.RA119.010720. doi: 10.1074/jbc.RA119.010720.

Bender, D., Kaczmarek, A.T., Santamaria-Araujo, J.A., Stueve, B., Waltz, S., Bartsch, D., Kurian, L., Cirak, S., and Schwarz, G. (2019). Impaired mitochondrial maturation of sulfite oxidase in a patient with severe sulfite oxidase deficiency. Hum. Mol. Genet. 28, 2885-2899.

Bender, D., Kaczmarek, AT., Niks, D., Hille, R., and Schwarz, G. (2019). Mechanism of nitrite-dependent NO synthesis by human sulfite oxidase. Biochem. J. 476, 1805-1815.

Kohl, J.B., Mellis, A.T., and Schwarz, G. (2019). Homeostatic impact of sulfite and hydrogen sulfide on cysteine catabolism. Br. J. Pharmacol. 176, 554-570.

Kaczmarek, A.T., Strampraad, M.J.F., Hagedoorn, P.L., and Schwarz, G. (2019). Reciprocal regulation of sulfite oxidation and nitrite reduction by mitochondrial sulfite oxidase. Nitric Oxide. 89, 22-31.

Zivanovic, J., Kouroussis, E., Kohl, J.B., ... Schwarz, G., Snyder, S.H., Paul, B.D., Carroll, K.S., Filipovic, M.R. (2019). Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration. Cell Metab. 30, 1152-1170.e13.

Bender, D., and Schwarz, G. (2018). Nitrite-dependent nitric oxide synthesis by molybdenum enzymes. FEBS Lett. 592, 2126-2139.

Kumar, A. Dejanovic, B., Hetsch, F., Semtner, M., Fusca, D., Arjune, S., Santamaria-Araujo, J.A., Winkelmann, A., Ayton, S., Bush, A.I., Kloppenburg, P., Meier, J.C., Schwarz, G., and Belaidi, A.A. (2017). S-sulfocysteine/NMDA receptor-dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency. J. Clin. Invest. 127, 4365-4378.

Schwarz, G. (2016). Molybdenum cofactor and human disease. Curr. Opin. Chem. Biol. 31, 179-187.

Schwahn, B.C., Van Spronsen, F.J., Belaidi, A.A., Bowhay, S., Christodoulou, J., Derks, T.G., Hennermann, J.B., Jameson, E., Konig, K., McGregor, T.L., et al. Schwarz, G.* (2015). Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet 386, 1955-1963. * corresponding author