A Small Molecule to Reduce Mitochondrial Generation of Oxidative Stress
Researchers here report on an improved version of compounds known to reduce the generation of oxidizing molecules by mitochondria. Mitochondrial dysfunction can produce sustained oxidative stress that changes cell behavior for the worse, contributing to aspects of aging. That targeting antioxidants to the mitochondria or upregulating natural antioxidant molecules can produce some benefit to health suggests that the size of the contribution is meaningful. The details matter, however, and as cells use mild mitochondrial oxidative stress to trigger beneficial maintenance activities, with the metabolic response to exercise being one example of this in action, one can't just take a blunt approach to the problem and expect benefits to result. That the approach here works for mitochondrial dysfunction in the context of obesity doesn't necessarily mean it will work well in the context of aging.
Numerous mechanisms and pathways have been suggested to initiate metabolic syndrome and the eventual development of specific diseases. In particular, there is a wealth of literature connecting metabolic syndrome to increased mitochondrial reactive oxygen species (ROS). The most compelling evidence comes from genetic manipulations in mice. Expression or overexpression of enzymes that determine the superoxide and hydrogen peroxide concentrations in the mitochondrial matrix (superoxide dismutase 2, SOD2; peroxiredoxin 3, PRDX3; mitochondria-targeted catalase, mCAT) are all strongly protective. Further support comes from the use of less specific mitochondria-targeted antioxidants (mitoQ, mitoVitE), and of the peptide SS-31. These lines of evidence strongly implicate mitochondria as the source of superoxide/hydrogen peroxide.
Eleven different sites of superoxide/hydrogen peroxide production associated with the mitochondrial electron transport chain have been identified. Of these, site IQ in complex I, site IIIQo in complex III, and site IIF in complex II have the greatest maximum capacities to generate superoxide/hydrogen peroxide in vitro. Compounds have been identified that specifically suppress superoxide/hydrogen peroxide production from site IQ (Suppressors of Site IQ Electron Leak, S1QELs) and site IIIQo (Suppressors of Site IIIQo Electron Leak, S3QELs) without inhibiting the electron transport chain or affecting oxidative phosphorylation. S1QELs and S3QELs have profound protective effects in cell and organ models, demonstrating the biological importance of superoxide/hydrogen peroxide production from sites IQ and IIIQo.
Existing S1QELs and S3QELs are not well suited for systemic in vivo use because of their poor solubility and bioavailability, although they can be added to the diet to affect gut cell function in flies and mice. WHere, we introduce a novel potent, selective and orally bioavailable S1QEL1: S1QEL1.719. S1QEL1.719 was used to test the metabolic effects of suppressing superoxide/hydrogen peroxide production from site IQ in vivo. C57BL/6J male mice fed a high-fat chow for one, two or eight weeks had increased body fat, decreased glucose tolerance, and increased fasting insulin concentrations, classic symptoms of metabolic syndrome. Daily prophylactic or therapeutic oral treatment of high-fat-fed animals with S1QEL1.719 decreased fat accumulation, strongly protected against decreased glucose tolerance and prevented or reversed the increase in fasting insulin level.