The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice.

TitleThe mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice.
Publication TypeJournal Article
Year of Publication2012
AuthorsMercer, JR, Yu, E, Figg, N, Cheng, K-K, Prime, TA, Griffin, JL, Masoodi, M, Vidal-Puig, A, Murphy, MP, Bennett, MR
JournalFree Radic Biol Med
Volume52
Issue5
Pagination841-9
Date Published2012 Mar 1
ISSN1873-4596
KeywordsAdiposity, Animals, Antioxidants, Apolipoproteins E, Ataxia Telangiectasia Mutated Proteins, Atherosclerosis, Blood Glucose, Cell Cycle Proteins, Cells, Cultured, Diet, High-Fat, DNA-Binding Proteins, Energy Metabolism, Female, Lipid Metabolism, Lipids, Liver, Male, Metabolic Syndrome X, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Organ Size, Organophosphorus Compounds, Oxidative Stress, Oxygen Consumption, Plaque, Atherosclerotic, Protein Carbonylation, Protein-Serine-Threonine Kinases, Reactive Oxygen Species, Tumor Suppressor Proteins, Ubiquinone
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.

DOI10.1016/j.freeradbiomed.2011.11.026
Alternate JournalFree Radic. Biol. Med.
Citation Key10.1016/j.freeradbiomed.2011.11.026
PubMed ID22210379
Grant List072829/Z/03/Z / / Wellcome Trust / United Kingdom
G0802051 / / Medical Research Council / United Kingdom
MC_U105663142 / / Medical Research Council / United Kingdom
MC_UP_A090_1006 / / Medical Research Council / United Kingdom
PG/05/08 / / British Heart Foundation / United Kingdom
RG/08/009/25841 / / British Heart Foundation / United Kingdom
RG08/009/25841 / / British Heart Foundation / United Kingdom
/ / Biotechnology and Biological Sciences Research Council / United Kingdom
/ / Medical Research Council / United Kingdom