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(The FASEB Journal. 2005;19:1088-1095.)
© 2005 FASEB

Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury

Victoria J. Adlam*,¶, Joanne C. Harrison, Carolyn M. Porteous§, Andrew M. James{dagger}, Robin A. J. Smith*, Michael P. Murphy{dagger},1 and Ivan A. Sammut

* Department of Chemistry,
Department of Pharmacology and Toxicology, and
§ Department of Biochemistry, University of Otago, Dunedin, New Zealand; and
{dagger} Medical Research Council Dunn Human Nutrition Unit, Cambridge, UK

1 Correspondence: MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 2XY, UK. E-mail: mpm{at}mrc-dunn.cam.ac.uk

Mitochondrial oxidative damage contributes to a wide range of pathologies, including cardiovascular disorders and neurodegenerative diseases. Therefore, protecting mitochondria from oxidative damage should be an effective therapeutic strategy. However, conventional antioxidants have limited efficacy due to the difficulty of delivering them to mitochondria in situ. To overcome this problem, we developed mitochondria-targeted antioxidants, typified by MitoQ, which comprises a lipophilic triphenylphosphonium (TPP) cation covalently attached to a ubiquinol antioxidant. Driven by the large mitochondrial membrane potential, the TPP cation concentrates MitoQ several hundred-fold within mitochondria, selectively preventing mitochondrial oxidative damage. To test whether MitoQ was active in vivo, we chose a clinically relevant form of mitochondrial oxidative damage: cardiac ischemia-reperfusion injury. Feeding MitoQ to rats significantly decreased heart dysfunction, cell death, and mitochondrial damage after ischemia-reperfusion. This protection was due to the antioxidant activity of MitoQ within mitochondria, as an untargeted antioxidant was ineffective and accumulation of the TPP cation alone gave no protection. Therefore, targeting antioxidants to mitochondria in vivo is a promising new therapeutic strategy in the wide range of human diseases such as Parkinson’s disease, diabetes, and Friedreich’s ataxia where mitochondrial oxidative damage underlies the pathology.—Adlam, V. J., Harrison, J. C., Porteous, C. M., James, A. M., Smith, R. A. J., Murphy, M. P., Sammut, I. A. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury.


Key Words: TPP • oxidative damage • MitoQ




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