The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice.
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.
Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
John R
JR
Mercer
Emma
E
Yu
Nichola
N
Figg
Kian-Kai
KK
Cheng
Tracy A
TA
Prime
Julian L
JL
Griffin
Mojgan
M
Masoodi
Antonio
A
Vidal-Puig
Michael P
MP
Murphy
Martin R
MR
Bennett
D050154:Adiposity / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001786:Blood Glucose / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008099:Liver / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D050050:Protein Carbonylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000975:Antioxidants; D001057:Apolipoproteins E; D001786:Blood Glucose; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008055:Lipids; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D014451:Ubiquinone; C429014:mitoquinone; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases