Targeting antioxidants to mitochondria by conjugation to lipophilic cations.
Mitochondrial oxidative damage contributes to a range of degenerative diseases. Consequently, the selective inhibition of mitochondrial oxidative damage is a promising therapeutic strategy. One way to do this is to invent antioxidants that are selectively accumulated into mitochondria within patients. Such mitochondria-targeted antioxidants have been developed by conjugating the lipophilic triphenylphosphonium cation to an antioxidant moiety, such as ubiquinol or alpha-tocopherol. These compounds pass easily through all biological membranes, including the blood-brain barrier, and into muscle cells and thus reach those tissues most affected by mitochondrial oxidative damage. Furthermore, because of their positive charge they are accumulated several-hundredfold within mitochondria driven by the membrane potential, enhancing the protection of mitochondria from oxidative damage. These compounds protect mitochondria from damage following oral delivery and may therefore form the basis for mitochondria-protective therapies. Here we review the background and work to date on this class of mitochondria-targeted antioxidants.
Murphy
Michael P
MP
MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge CB2 2XY, United Kingdom. mpm@mrc-dunn.cam.ac.uk
Smith
Robin A J
RA
D000975:Antioxidants / Q000493:pharmacokinetics* / Q000494:pharmacology; D002412:Cations / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014018:Tissue Distribution
D000975:Antioxidants; D002412:Cations; D004337:Drug Carriers; D017382:Reactive Oxygen Species