PUBLICATION
Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease
- Authors
- Guha, S., Konkwo, C., Lavorato, M., Mathew, N.D., Peng, M., Ostrovsky, J., Kwon, Y.J., Polyak, E., Lightfoot, R., Seiler, C., Xiao, R., Bennett, M., Zhang, Z., Nakamaru-Ogiso, E., Falk, M.J.
- ID
- ZDB-PUB-190123-6
- Date
- 2019
- Source
- Human molecular genetics 28(11): 1837-1852 (Journal)
- Registered Authors
- Seiler, Christoph
- Keywords
- none
- MeSH Terms
-
- Animals
- Antioxidants/pharmacology*
- Brain Death/metabolism
- Brain Death/pathology
- Caenorhabditis elegans/drug effects
- Caenorhabditis elegans/genetics
- 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
- Glutathione/metabolism
- Humans
- Hydrogen Peroxide
- Membrane Potential, Mitochondrial/drug effects
- Mitochondrial Diseases/drug therapy*
- Mitochondrial Diseases/genetics
- Mitochondrial Diseases/pathology
- NADH Dehydrogenase/genetics*
- Oxidative Stress/drug effects
- Ubiquitin-Protein Ligases/genetics
- Zebrafish/genetics
- PubMed
- 30668749 Full text @ Hum. Mol. Genet.
Citation
Guha, S., Konkwo, C., Lavorato, M., Mathew, N.D., Peng, M., Ostrovsky, J., Kwon, Y.J., Polyak, E., Lightfoot, R., Seiler, C., Xiao, R., Bennett, M., Zhang, Z., Nakamaru-Ogiso, E., Falk, M.J. (2019) Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease. Human molecular genetics. 28(11):1837-1852.
Abstract
Cysteamine bitartrate is an FDA-approved therapy for nephropathic cystinosis 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 evolutionary 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 C. 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) D. rerio vertebrate zebrafish models from brain death. Mechanistic profiling of cysteamine bitartrate effects showed it increases aspartate levels and flux, without increasing total glutathione levels. Transcriptional normalization was greater in RC disease human cells than C. elegans of broadly dysregulated intermediary metabolic, glutathione, cell defense, DNA, and immune pathways, with similar rescue in both models of downregulated ribosome and proteasome 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping