PUBLICATION
Combinatorial glucose, nicotinic acid, and N-acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease
- Authors
- Guha, S., Mathew, N.D., Konkwo, C., Ostrovsky, J., Kwon, Y.J., Polyak, E., Seiler, C., Bennett, M., Xiao, R., Zhang, Z., Nakamaru-Ogiso, E., Falk, M.J.
- ID
- ZDB-PUB-210302-4
- Date
- 2021
- Source
- Human molecular genetics 30(7): 536-551 (Journal)
- Registered Authors
- Seiler, Christoph
- Keywords
- none
- MeSH Terms
-
- Acetylcysteine/pharmacology*
- Animals
- Caenorhabditis elegans
- Disease Models, Animal*
- Drug Synergism
- Electron Transport Complex I/genetics
- Electron Transport Complex I/metabolism*
- Free Radical Scavengers/pharmacology
- Glucose/pharmacology*
- Humans
- Longevity/drug effects
- Longevity/genetics
- Membrane Potential, Mitochondrial/drug effects
- Mitochondria/drug effects*
- Mitochondria/genetics
- Mitochondria/metabolism
- Mitochondrial Diseases/genetics
- Mitochondrial Diseases/metabolism
- Mitochondrial Diseases/prevention & control*
- Mutation
- Niacin/pharmacology*
- Oxidative Stress/drug effects
- Zebrafish
- PubMed
- 33640978 Full text @ Hum. Mol. Genet.
Citation
Guha, S., Mathew, N.D., Konkwo, C., Ostrovsky, J., Kwon, Y.J., Polyak, E., Seiler, C., Bennett, M., Xiao, R., Zhang, Z., Nakamaru-Ogiso, E., Falk, M.J. (2021) Combinatorial glucose, nicotinic acid, and N-acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease. Human molecular genetics. 30(7):536-551.
Abstract
Mitochondrial respiratory chain disorders are empirically managed with variable antioxidant, cofactor, and vitamin 'cocktails'. However, clinical trial validated and approved compounds, or doses, do not exist for any single or combinatorial mitochondrial disease therapy. Here, we sought to pre-clinically evaluate whether rationally-designed mitochondrial medicine combinatorial regimens might synergistically improve survival, health, and physiology in translational animal models of respiratory chain complex I disease. Having previously demonstrated that gas-1(fc21) complex I subunit NDUFS2-/- C. elegans have short lifespan that can be significantly rescued with 17 different metabolic modifiers, signaling modifiers, or antioxidants, here we evaluated 11 random combinations of these 3 treatment classes on gas-1(fc21) lifespan. Synergistic rescue occurred only with glucose, nicotinic acid, and N-acetylcysteine (Glu + NA + NAC), yielding improved mitochondrial membrane potential that reflects integrated respiratory chain function, without exacerbating oxidative stress and while reducing mitochondrial stress (UPRmt) and improving intermediary metabolic disruptions at the levels of the transcriptome, steady-state metabolites, and intermediary metabolic flux. Equimolar Glu + NA + NAC dosing in a zebrafish vertebrate model of rotenone-based complex I inhibition synergistically rescued larval activity, brain death, lactate, ATP, and glutathione levels. Overall, these data provide objective preclinical evidence in two evolutionary-divergent animal models of mitochondrial complex I disease to demonstrate that combinatorial Glu + NA + NAC therapy significantly improved animal resiliency in the face of stressors that exacerbate their underlying metabolic deficiency, thereby preventing acute neurologic and biochemical decompensation. Clinical trials are warranted to evaluate the efficacy of this lead combinatorial therapy regimen to improve resiliency and health outcomes in human subjects with mitochondrial disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping