Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease.
Animals
Antioxidants
/ pharmacology
Brain Death
/ metabolism
Caenorhabditis elegans
/ drug effects
Caenorhabditis elegans Proteins
/ genetics
Cysteamine
/ pharmacology
Dose-Response Relationship, Drug
Electron Transport
/ drug effects
F-Box Proteins
/ genetics
Fertility
/ drug effects
Fibroblasts
/ drug effects
Glutathione
/ genetics
Humans
Hydrogen Peroxide
Membrane Potential, Mitochondrial
/ drug effects
Mitochondrial Diseases
/ drug therapy
NADH Dehydrogenase
/ genetics
Oxidative Stress
/ drug effects
Ubiquitin-Protein Ligases
/ genetics
Zebrafish
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
received:
30
10
2018
revised:
15
01
2019
accepted:
17
01
2019
pubmed:
23
1
2019
medline:
7
2
2020
entrez:
23
1
2019
Statut:
ppublish
Résumé
Cysteamine bitartrate is a US Food and Drug Administration-approved therapy for nephropathic cystinosis also postulated to enhance glutathione biosynthesis. We hypothesized this antioxidant effect may reduce oxidative stress in primary mitochondrial respiratory chain (RC) disease, improving cellular viability and organismal health. Here, we systematically evaluated the therapeutic potential of cysteamine bitartrate in RC disease models spanning three evolutionarily distinct species. These pre-clinical studies demonstrated the narrow therapeutic window of cysteamine bitartrate, with toxicity at millimolar levels directly correlating with marked induction of hydrogen peroxide production. Micromolar range cysteamine bitartrate treatment in Caenorhabditis elegans gas-1(fc21) RC complex I (NDUFS2-/-) disease invertebrate worms significantly improved mitochondrial membrane potential and oxidative stress, with corresponding modest improvement in fecundity but not lifespan. At 10 to 100 μm concentrations, cysteamine bitartrate improved multiple RC complex disease FBXL4 human fibroblast survival, and protected both complex I (rotenone) and complex IV (azide) Danio rerio vertebrate zebrafish disease models from brain death. Mechanistic profiling of cysteamine bitartrate effects showed it increases aspartate levels and flux, without increasing total glutathione levels. Transcriptional normalization of broadly dysregulated intermediary metabolic, glutathione, cell defense, DNA, and immune pathways was greater in RC disease human cells than in C. elegans, with similar rescue in both models of downregulated ribosomal and proteasomal pathway expression. Overall, these data suggest cysteamine bitartrate may hold therapeutic potential in RC disease, although not through obvious modulation of total glutathione levels. Careful consideration is required to determine safe and effective cysteamine bitartrate concentrations to further evaluate in clinical trials of human subjects with primary mitochondrial RC disease.
Identifiants
pubmed: 30668749
pii: 5298534
doi: 10.1093/hmg/ddz023
pmc: PMC6522065
doi:
Substances chimiques
Antioxidants
0
Caenorhabditis elegans Proteins
0
F-Box Proteins
0
Cysteamine
5UX2SD1KE2
Hydrogen Peroxide
BBX060AN9V
NADH Dehydrogenase
EC 1.6.99.3
Ubiquitin-Protein Ligases
EC 2.3.2.27
FbxL4 protein, human
EC 6.3.2.-
GAS-1 protein, C elegans
EC 7.1.1.2
NDUFS2 protein, human
EC 7.1.1.2
Glutathione
GAN16C9B8O
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1837-1852Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM120762
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS007413
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD086984
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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