N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease

Polyak, E., Ostrovsky, J., Peng, M., Dingley, S.D., Tsukikawa, M., Kwon, Y.J., McCormack, S.E., Bennett, M., Xiao, R., Seiler, C., Zhang, Z., Falk, M.J.
Molecular genetics and metabolism   123(4): 449-462 (Journal)
Registered Authors
Seiler, Christoph
Antioxidant, C. elegans, Fibroblasts, genetic disease, Mitochondria, Therapeutic modeling, Zebrafish
MeSH Terms
  • Acetylcysteine/pharmacology*
  • Animals
  • Animals, Genetically Modified
  • Antioxidants/pharmacology
  • Caenorhabditis elegans
  • Cells, Cultured
  • Drug Evaluation, Preclinical*
  • Electron Transport Complex I/genetics
  • Electron Transport Complex I/metabolism*
  • Fibroblasts/drug effects
  • Fibroblasts/metabolism
  • Fibroblasts/pathology
  • Free Radical Scavengers/pharmacology
  • Humans
  • Longevity*
  • Mitochondria/drug effects
  • Mitochondria/metabolism
  • Mitochondria/pathology
  • Mitochondrial Diseases/drug therapy*
  • Mitochondrial Diseases/genetics
  • Mitochondrial Diseases/metabolism
  • Mitochondrial Diseases/pathology
  • Mutant Proteins/genetics
  • Mutant Proteins/metabolism
  • Mutation
  • Oxidative Stress/drug effects*
  • Vitamin E/pharmacology*
29526616 Full text @ Mol. Genet. Metab.
Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes