Abstract
Short-chain quinones have been investigated as therapeutic molecules due to their ability to modulate cellular redox reactions, mitochondrial electron transfer and oxidative stress, which are pathologically altered in many mitochondrial and neuromuscular disorders. Recently, we and others described that certain short-chain quinones are able to bypass a deficiency in complex I by shuttling electrons directly from the cytoplasm to complex III of the mitochondrial respiratory chain to produce ATP. Although this energy rescue activity is highly interesting for the therapy of disorders associated with complex I dysfunction, no structure-activity-relationship has been reported for short-chain quinones so far. Using a panel of 70 quinones, we observed that the capacity for this cellular energy rescue as well as their effect on lipid peroxidation was influenced more by the physicochemical properties (in particular logD) of the whole molecule than the quinone moiety itself. Thus, the observed correlations allow us to explain the differential biological activities and therapeutic potential of short-chain quinones for the therapy of disorders associated with mitochondrial complex I dysfunction and/or oxidative stress.
Highlights
Quinones, such as coenzyme Q10 (CoQ10) or vitamin K are a chemical class of compounds containing a quinoid ring system; reviewed by [1,2] causing them to be involved in a vast range of cellular redox reactions
This electron transfer involves the reduction of quinones by cytoplasmic NQO1 or related reductases, which is associated with a reduction of cellular NADH levels [21]
For some-short chain quinones described here, bioactivation is associated with a protection of cellular adenosine triphosphate (ATP) levels under conditions of impaired complex I function [6,21,22] and reduced levels of lipid peroxidation
Summary
Quinones, such as coenzyme Q10 (CoQ10) or vitamin K are a chemical class of compounds containing a quinoid ring system; reviewed by [1,2] causing them to be involved in a vast range of cellular redox reactions. NAD(P)H:quinone oxidoreductases (NQOs) on the other hand are cytosolic flavoproteins that compete with P450 reductase and catalyze the reduction of quinones and their derivates by complete, two-electron reduction [2]. This process leads to relatively stable hydroquinones, often referred to as quinols, which does not result in the formation of ROS. NQOs are able to efficiently reduce CoQ0 [5] and CoQ1 [6,7] These quinones are short-chain analogs of CoQ10, which is best known for its pivotal role in mitochondrial oxidative phosphorylation, the functional significance of NQOdependent reduction of CoQ0 and CoQ1 is still unclear
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