B08 | Sulfite-dependent regulation of mitochondrial function by sulfite oxidase
Günter Schwarz
Institute for Biochemistry
University of Cologne
E-mail: gschwarz
uni-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 - 06/2028.
Abstract
Mitochondrial sulfite oxidase (SOX) is the most important molybdenum-dependent enzyme in humans. It catalyses the final step in cysteine catabolism within the intermembrane space of mitochondria. A deficiency in SOX is associated with rapidly progressing neurodegeneration resulting in most cases in early childhood death. Our mouse model developed for SOX deficiency (SOXD) disclosed an unexpected accumulation of H2S as novel hallmark of the disease. In the third funding period we aim to understand the mechanistic basis how H2S and altered persulfidation affecting mitochondria in different tissues of Suox–/– mice.
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