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Overproduction of H2S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome.
Proc Natl Acad Sci U S A. 2019 09 17; 116(38):18769-18771.PN

Abstract

Down syndrome (DS) is associated with significant perturbances in mitochondrial function. Here we tested the hypothesis that the suppression of mitochondrial electron transport in DS cells is due to high expression of cystathionine-β-synthase (CBS) and subsequent overproduction of the gaseous transmitter hydrogen sulfide (H2S). Fibroblasts from DS individuals showed higher CBS expression than control cells; CBS localization was both cytosolic and mitochondrial. DS cells produced significantly more H2S and polysulfide and exhibited a profound suppression of mitochondrial electron transport, oxygen consumption, and ATP generation. DS cells also exhibited slower proliferation rates. In DS cells, pharmacological inhibition of CBS activity with aminooxyacetate or siRNA-mediated silencing of CBS normalized cellular H2S levels, restored Complex IV activity, improved mitochondrial electron transport and ATP synthesis, and restored cell proliferation. Thus, CBS-derived H2S is responsible for the suppression of mitochondrial function in DS cells. When H2S overproduction is corrected, the tonic suppression of Complex IV is lifted, and mitochondrial electron transport is restored. CBS inhibition offers a potential approach for the pharmacological correction of DS-associated mitochondrial dysfunction.

Authors+Show Affiliations

Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland.Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland.Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland.Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland csaba.szabo@unifr.ch.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31481613

Citation

Panagaki, Theodora, et al. "Overproduction of H2S, Generated By CBS, Inhibits Mitochondrial Complex IV and Suppresses Oxidative Phosphorylation in Down Syndrome." Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 38, 2019, pp. 18769-18771.
Panagaki T, Randi EB, Augsburger F, et al. Overproduction of H2S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome. Proc Natl Acad Sci U S A. 2019;116(38):18769-18771.
Panagaki, T., Randi, E. B., Augsburger, F., & Szabo, C. (2019). Overproduction of H2S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome. Proceedings of the National Academy of Sciences of the United States of America, 116(38), 18769-18771. https://doi.org/10.1073/pnas.1911895116
Panagaki T, et al. Overproduction of H2S, Generated By CBS, Inhibits Mitochondrial Complex IV and Suppresses Oxidative Phosphorylation in Down Syndrome. Proc Natl Acad Sci U S A. 2019 09 17;116(38):18769-18771. PubMed PMID: 31481613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overproduction of H2S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome. AU - Panagaki,Theodora, AU - Randi,Elisa B, AU - Augsburger,Fiona, AU - Szabo,Csaba, Y1 - 2019/09/03/ PY - 2019/9/5/pubmed PY - 2020/4/1/medline PY - 2019/9/5/entrez KW - H2S KW - bioenergetics KW - metabolism KW - mitochondria SP - 18769 EP - 18771 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 116 IS - 38 N2 - Down syndrome (DS) is associated with significant perturbances in mitochondrial function. Here we tested the hypothesis that the suppression of mitochondrial electron transport in DS cells is due to high expression of cystathionine-β-synthase (CBS) and subsequent overproduction of the gaseous transmitter hydrogen sulfide (H2S). Fibroblasts from DS individuals showed higher CBS expression than control cells; CBS localization was both cytosolic and mitochondrial. DS cells produced significantly more H2S and polysulfide and exhibited a profound suppression of mitochondrial electron transport, oxygen consumption, and ATP generation. DS cells also exhibited slower proliferation rates. In DS cells, pharmacological inhibition of CBS activity with aminooxyacetate or siRNA-mediated silencing of CBS normalized cellular H2S levels, restored Complex IV activity, improved mitochondrial electron transport and ATP synthesis, and restored cell proliferation. Thus, CBS-derived H2S is responsible for the suppression of mitochondrial function in DS cells. When H2S overproduction is corrected, the tonic suppression of Complex IV is lifted, and mitochondrial electron transport is restored. CBS inhibition offers a potential approach for the pharmacological correction of DS-associated mitochondrial dysfunction. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/31481613/Overproduction_of_H2S_generated_by_CBS_inhibits_mitochondrial_Complex_IV_and_suppresses_oxidative_phosphorylation_in_Down_syndrome_ L2 - http://www.pnas.org/lookup/pmidlookup?view=long&pmid=31481613 DB - PRIME DP - Unbound Medicine ER -