The Mitochondria-Targeted Antioxidant MitoQ Extends Lifespan and Improves Healthspan of a Transgenic Caenorhabditis Elegans Model of Alzheimer Disease

Free Radic Biol Med. 2014 Jun;71:390-401. doi: 10.1016/j.freeradbiomed.2014.03.003. Epub 2014 Mar 15.

Abstract

β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD.

Keywords: Alzheimer disease; Caenorhabditis elegans; Cardiolipin; Complex IV; Cytochrome c oxidase; Electron transport chain; Free radicals; Healthspan; Lifespan; MitoQ; Mitochondria-targeted antioxidants; Oxidative stress; β-Amyloid peptides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / biosynthesis
  • Amyloid beta-Peptides / genetics
  • Animals
  • Antioxidants / pharmacology*
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Disease Models, Animal
  • Electron Transport Chain Complex Proteins / agonists
  • Electron Transport Chain Complex Proteins / metabolism
  • Gene Expression
  • Humans
  • Longevity / drug effects*
  • Mitochondria / drug effects*
  • Mitochondria / enzymology
  • Mitochondria / pathology
  • Mitochondrial Membranes / drug effects
  • Organophosphorus Compounds / pharmacology*
  • Oxidative Stress
  • Oxygen Consumption
  • Protein Carbonylation
  • Reactive Oxygen Species / antagonists & inhibitors*
  • Reactive Oxygen Species / metabolism
  • Transgenes
  • Ubiquinone / analogs & derivatives*
  • Ubiquinone / pharmacology

Substances

  • 10-(6'-ubiquinonyl)decyltriphenylphosphonium bromide
  • Amyloid beta-Peptides
  • Antioxidants
  • Electron Transport Chain Complex Proteins
  • Organophosphorus Compounds
  • Reactive Oxygen Species
  • Ubiquinone
  • Adenosine Triphosphate