Multifunctional Radical Quenchers as Mitochondrial Therapeutic Agents
Sidney M. Hecht

Center for BioEnergetics, Biodesign Institute, and Department of Chemistry
and Biochemistry Arizona State University, Tempe, Arizona, USA

In humans, the major source of energy used to drive biochemical processes is ATP. We produce and consume about 50 moles of ATP/day. Most of our ATP is produced by oxidative phosphorylation in the mitochondria, within the respiratory chain. There are a number of diseases in which mitochondrial function is impaired. These are associated with increased oxidative stress, degradation of cellular macromolecules, and decreased ATP production. The most prevalent inherited respiratory chain disorder is Friedreich's ataxia, which afflicts about 1 in 50,000 individuals in the United States. It results from a deficiency of the enzyme frataxin, which is responsible for assembly of the Fe-S clusters in numerous proteins within the individual complexes of the mitochondrial respiratory chain.

There is currently no approved treatment for Friedreich's ataxia. The objective of this work is to design, prepare and study analogues of the normal mitochondrial electron carrier coenzyme Q10. The modified electron carriers are designed to suppress oxidative stress, and diminish the degradation of cellular macromolecules, in addition to supporting ATP synthesis. Because they suppress one-electron trafficking in dysfunctional mitochondria, with multiple beneficial effects, we denote them multifunctional radical quenchers. These agents may be broadly applicable to the treatment of additional neurological diseases, and diseases having a component of energetic dysfunction involving mitochondrial respiration.