Abstract
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.
Highlights
Departments of Pediatrics and Pathology, Stanford University, 300 Pasteur Drive, H-315, Stanford, Academic Editor: Iain P
The ability to quantify mitochondrial dysfunction in an affected patient will help with routine care, and improve rational clinical trial design aimed at developing new therapies
Abnormal mitochondrial structure and function, as well as various abnormal measures of oxidative stress and redox imbalance, have been reported in animal models and patients affected by a variety of organic acidemias, including methylmalonic acidemia, cobalamin A disease, cobalamin C disease, cobalamin H/cobalamin D disease, propionic acidemia, isovaleric acidemia, 2-methyl-3-hydroxybutyric acidemia, 3-methylglutaconic acidemia types II and IV, D-2-hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria, and glutaric acidemia [42,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70]
Summary
“Do you feel any better?” is a commonly asked question by a physician caring for a patient who has an underlying mitochondrial disorder during a clinic visit, typically after an interval of time following the start of various co-factors, vitamins, or supplements that may have a beneficial effect on mitochondrial function [1]. Recent discoveries of minimally-invasive mitochondrial biomarkers, including blood creatine, FGF-21, and GDF-15, provide increased sensitivity and specificity compared to the standard practice of measuring lactate [8,9,10,11], the link between these new biomarkers and mitochondrial disease pathophysiology is still unclear. In contrast to these new analytes, which were detected by global metabolomic or transcriptomic profiling [9,12,13], there is a clear theoretical link between pathophysiology and biomarkers that are directly related to the biochemistry of redox imbalance. The ability to quantify mitochondrial dysfunction in an affected patient will help with routine care, and improve rational clinical trial design aimed at developing new therapies
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