Prevention of Mitochondrial Oxidative Damage Using Targeted Antioxidants

Abstract

Mitochondrial-targeted antioxidants that selectively block mitochondrial oxidative damage and prevent some types of cell death have been developed. These antioxidants are ubiquinone and tocopherol derivatives and are targeted to mitochondria by covalent attachment to a lipophilic triphenylphosphonium cation. Because of the large mitochondrial membrane potential, these cations accumulated within mitochondria inside cells, where the antioxidant moiety prevents lipid peroxidation and protects mitochondria from oxidative damage. The mitochondrially localized ubiquinone also protected mammalian cells from hydrogen peroxide-induced apoptosis while an untargeted ubiquinone analogue was ineffective against apoptosis. When fed to mice these compounds accumulated within the brain, heart, and liver; therefore, using these mitochondrial-targeted antioxidants may help investigations of the role of mitochondrial oxidative damage in animal models of aging.

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

“…One such compound is triphenylphosphonium cation (TPP), which has been used for measuring the mitochondrial inner membrane potential. Estimates suggest that linking antioxidants to TPP increases their accumulation in the mitochondrial matrix by several hundred-fold [79][80][81]. Examples of such mitochondria-targeted antioxidants include MitoVitE (TPP coupled to alpha-tocopherol), Mito-Q (TPP coupled to ubiquinone), Mito-PBN (TPP coupled to PBN), and Mito-CP (TPP coupled to carboxy-proxyl nitroxide).…”

Pulsing of Membrane Potential in Individual Mitochondria: A Stress-Induced Mechanism to Regulate Respiratory Bioenergetics in Arabidopsis

“…Furthermore, pulsing was significantly inhibited by preincubation with mitoQ, a mitochondrial antioxidant (Kelso et al, 2001(Kelso et al, , 2002, raising the possibility that ROS may induce pulsing, possibly by activating the ion channel responsible. While other antioxidants increased pulsing rates, the specificity and distribution of these compounds is likely to be different, with mitoQ partitioning into the membrane, and this might provide an explanation for the differential effects.…”

“…The involvement of Ca 2+ is further supported by the inhibitory effect of EGTA on pulsing. MitoQ is a mitochondrial antioxidant (Kelso et al, 2001(Kelso et al, , 2002 and also caused a significant decrease in pulsing ( Figure 4B). Interestingly, other antioxidants, such as dithioerythritol and GSH, showed the opposite effect.…”

Spinocerebellar degeneration

“…Open-label [36][37][38][39] and controlled trials [37,40] of these agents have shown some benefit for cardiac and muscle parameters but no improvement in ataxia. A National Institute of Neurological Disorders and Stroke-sponsored Phase I study of higher doses of idebenone is currently in progress and a safety and tolerability study of mitoquinone, ubiquinone conjugated to a lipophilic cation that will enhance its mitochondrial uptake, is planned [41]. The use of mitochondrially-targeted iron chelators has also been proposed [42].…”