Article

Consequences of long-term oral administration of the mitochondria-targeted antioxidant MitoQ to wild-type mice

Department of Clinical Biochemistry, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, UK; Medical Research Council Mitochondrial Biology Unit, Cambridge CB2 0XY, UK; Institute of Healthy Ageing and Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK; Genomics CoreLab, NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Cambridge CB2 0QQ, UK; Department of Chemistry, University of Otago, Dunedin 9054, New Zealand
Free Radical Biology and Medicine DOI:10.1016/j.freeradbiomed.2009.10.039 pp.161-172

ABSTRACT The mitochondria-targeted quinone MitoQ protects mitochondria in animal studies of pathologies in vivo and is being developed as a therapy for humans. However, it is unclear whether the protective action of MitoQ is entirely due to its antioxidant properties, because long-term MitoQ administration may alter whole-body metabolism and gene expression. To address this point, we administered high levels of MitoQ orally to wild-type C57BL/6 mice for up to 28 weeks and investigated the effects on whole-body physiology, metabolism, and gene expression, finding no measurable deleterious effects. In addition, because antioxidants can act as pro-oxidants under certain conditions in vitro, we examined the effects of MitoQ administration on markers of oxidative damage. There were no changes in the expression of mitochondrial or antioxidant genes as assessed by DNA microarray analysis. There were also no increases in oxidative damage to mitochondrial protein, DNA, or cardiolipin, and the activities of mitochondrial enzymes were unchanged. Therefore, MitoQ does not act as a pro-oxidant in vivo. These findings indicate that mitochondria-targeted antioxidants can be safely administered long-term to wild-type mice.

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    Article: The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice.
    John R Mercer, Emma Yu, Nichola Figg, Kian-Kai Cheng, Tracy A Prime, Julian L Griffin, Mojgan Masoodi, Antonio Vidal-Puig, Michael P Murphy, Martin R Bennett
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    ABSTRACT: A number of recent studies suggest that mitochondrial oxidative damage may be associated with atherosclerosis and the metabolic syndrome. However, much of the evidence linking mitochondrial oxidative damage and excess reactive oxygen species (ROS) with these pathologies is circumstantial. Consequently the importance of mitochondrial ROS in the etiology of these disorders is unclear. Furthermore, the potential of decreasing mitochondrial ROS as a therapy for these indications is not known. We assessed the impact of decreasing mitochondrial oxidative damage and ROS with the mitochondria-targeted antioxidant MitoQ in models of atherosclerosis and the metabolic syndrome (fat-fed ApoE(-/-) mice and ATM(+/-)/ApoE(-/-) mice, which are also haploinsufficient for the protein kinase, ataxia telangiectasia mutated (ATM). MitoQ administered orally for 14weeks prevented the increased adiposity, hypercholesterolemia, and hypertriglyceridemia associated with the metabolic syndrome. MitoQ also corrected hyperglycemia and hepatic steatosis, induced changes in multiple metabolically relevant lipid species, and decreased DNA oxidative damage (8-oxo-G) in multiple organs. Although MitoQ did not affect overall atherosclerotic plaque area in fat-fed ATM(+/+)/ApoE(-/-) and ATM(+/-)/ApoE(-/-) mice, MitoQ reduced the macrophage content and cell proliferation within plaques and 8-oxo-G. MitoQ also significantly reduced mtDNA oxidative damage in the liver. Our data suggest that MitoQ inhibits the development of multiple features of the metabolic syndrome in these mice by affecting redox signaling pathways that depend on mitochondrial ROS such as hydrogen peroxide. These findings strengthen the growing view that elevated mitochondrial ROS contributes to the etiology of the metabolic syndrome and suggest a potential therapeutic role for mitochondria-targeted antioxidants.
    Free radical biology & medicine 12/2011; 52(5):841-9. · 5.42 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

animal studies
 
antioxidant genes
 
antioxidant properties
 
antioxidants
 
certain conditions
 
DNA microarray analysis
 
long-term
 
long-term MitoQ administration
 
measurable deleterious effects
 
mitochondria-targeted antioxidants
 
mitochondria-targeted quinone MitoQ
 
mitochondrial
 
mitochondrial enzymes
 
mitochondrial protein
 
MitoQ administration
 
MitoQ orally
 
oxidative damage
 
pro-oxidants
 
whole-body metabolism
 
whole-body physiology