Technical advances in the ability to measure mitochondrial dysfunction are providing new insights into mitochondrial disease pathogenesis, along with new tools to objectively evaluate the clinical status of mitochondrial disease patients. Glutathione (l-ϒ-glutamyl-l-cysteinylglycine) is the most abundant intracellular thiol, and the intracellular redox state, as reflected by levels of oxidized (GSSG) and reduced (GSH) glutathione, as well as the GSH/GSSG ratio, is considered to be an important indication of cellular health. The ability to quantify mitochondrial dysfunction in an affected patient will not only help with routine care, but also improve rational clinical trial design aimed at developing new therapies. Indeed, because multiple disorders have been associated with either primary or secondary deficiency of the mitochondrial electron transport chain and redox imbalance, developing mitochondrial therapies that have the potential to improve the intracellular glutathione status has been a focus of several clinical trials over the past few years. This review will also discuss potential therapies to increase intracellular glutathione with a focus on EPI-743 (α-tocotrienol quinone), a compound that appears to have the ability to modulate the activity of oxidoreductases, in particular NAD(P)H:quinone oxidoreductase 1.
Keywords: EPI-743; N-acetylcysteine; RP103; cysteamine; glutathione; mitochondrial disease; redox imbalance.