ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2025
Cyanide overproduction impairs cellular bioenergetics in Down syndrome.
Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Catechol-Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Tunable and self-reporting esterase-activated cyanide prodrugs exert cytoprotective effects.Nature communications · 2026Article
- Hydrogen Cyanide Generation by Pseudomonas aeruginosa Blunts the Host Innate Immune Response.The Journal of infectious diseases · 2026Article
- Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions.Antioxidants (Basel, Switzerland) · 2026Review
- Cyanide is an endogenous stimulator of endothelial cell proliferation, migration and differentiation.Experimental biology and medicine (Maywood, N.J.) · 2026Article
- Cystathionine γ-lyase is a major regulator of cognitive function through neurotrophin signaling and neurogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Gasotransmitter signaling in the brain: New frontiers for therapeutics.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Synergistic mitochondrial impairment by endogenously elevated cyanide and hydrogen sulfide in Down syndrome; commentary on: Cyanide overproduction impairs cellular bioenergetics in Down syndrome.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
Corrections and comments
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cyanide exerts its toxic effects primarily by inhibiting mitochondrial Complex IV (Cytochrome c oxidase, CCOx). Recent studies have shown that mammalian cells can endogenously produce cyanide from glycine via a lysosomal pathway. At low concentrations, cyanide may play regulatory roles, but at higher levels, it causes metabolic inhibition. Here we show that Down syndrome (DS) cells and tissues exhibit significant overproduction of cyanide, contributing to cellular metabolic suppression. DS rats show elevated blood cyanide levels, and their tissues generate more cyanide than wild-type controls-both under basal conditions and following glycine supplementation. Similarly, human DS fibroblasts produce higher levels of cyanide than healthy control cells. We attribute this increased cyanide production in DS to the marked downregulation of thiosulfate sulfurtransferase (TST, also known as rhodanese), the key enzyme responsible for cyanide detoxification. Importantly, suppression of lysosomal cyanide production in DS cells (through cyanide scavengers, lysosomal deacidification, or inhibition of serine/glycine conversion) improves cellular bioenergetics and/or enhances cell proliferation rates. Previous work has implicated excessive hydrogen sulfide (H
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.