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 Sep 17;116(38):18769-18771. doi: 10.1073/pnas.1911895116. Epub 2019 Sep 3.


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.

Keywords: H2S; bioenergetics; metabolism; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminooxyacetic Acid / pharmacology
  • Cell Proliferation
  • Cells, Cultured
  • Cystathionine beta-Synthase / antagonists & inhibitors
  • Cystathionine beta-Synthase / genetics
  • Cystathionine beta-Synthase / metabolism*
  • Down Syndrome / metabolism*
  • Down Syndrome / pathology
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism*
  • Energy Metabolism
  • Female
  • Fibroblasts / metabolism
  • Gene Expression
  • Humans
  • Hydrogen Sulfide / metabolism*
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Oxidative Phosphorylation
  • Oxygen Consumption
  • RNA, Small Interfering / genetics
  • Sulfides / metabolism


  • RNA, Small Interfering
  • Sulfides
  • Aminooxyacetic Acid
  • polysulfide
  • Electron Transport Complex IV
  • Cystathionine beta-Synthase
  • Hydrogen Sulfide