NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels.

Roman H Haefeli,Robert Dallmann,Nuri Gueven,Corinne Anklin,Isabelle Courdier Fruh,Anja C Gemperli,Michael Erb,Dimitri Robay,Annalisa Pastore

doi:10.1371/journal.pone.0017963

Abstract

Short-chain quinones are described as potent antioxidants and in the case of idebenone have already been under clinical investigation for the treatment of neuromuscular disorders. Due to their analogy to coenzyme Q10 (CoQ10), a long-chain quinone, they are widely regarded as a substitute for CoQ10. However, apart from their antioxidant function, this provides no clear rationale for their use in disorders with normal CoQ10 levels. Using recombinant NAD(P)H:quinone oxidoreductase (NQO) enzymes, we observed that contrary to CoQ10 short-chain quinones such as idebenone are good substrates for both NQO1 and NQO2. Furthermore, the reduction of short-chain quinones by NQOs enabled an antimycin A-sensitive transfer of electrons from cytosolic NAD(P)H to the mitochondrial respiratory chain in both human hepatoma cells (HepG2) and freshly isolated mouse hepatocytes. Consistent with the substrate selectivity of NQOs, both idebenone and CoQ1, but not CoQ10, partially restored cellular ATP levels under conditions of impaired complex I function. The observed cytosolic-mitochondrial shuttling of idebenone and CoQ1 was also associated with reduced lactate production by cybrid cells from mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) patients. Thus, the observed activities separate the effectiveness of short-chain quinones from the related long-chain CoQ10 and provide the rationale for the use of short-chain quinones such as idebenone for the treatment of mitochondrial disorders.

Highlights

Quinones, such as vitamin K or coenzyme Q10 (CoQ10), are a chemical class containing a quinoid ring system [reviewed by 1,2] as pharmacophore
Since we showed quinonedependent rescue of adenosine triphosphate (ATP) levels under conditions of impaired mitochondrial complex I function (Figure 3) and NQO1dependent metabolism is described to increase NAD+/NADH ratio [9], we investigated the role of quinones on cellular metabolism in cybrids harboring either wild type (WT) mitochondria or mitochondria from MELAS patients
We have described that short-chain quinones are excellent substrates for reduction by NQO1 and NQO2, which is generally in agreement with previous reports [8,40]

Summary

Introduction

Quinones, such as vitamin K or coenzyme Q10 (CoQ10), are a chemical class containing a quinoid ring system [reviewed by 1,2] as pharmacophore. Enzymes involved in cellular quinone metabolism catalyze mainly two different redox reactions. Since semiquinones can react with molecular oxygen to generate reactive oxygen species (ROS), this process can lead to oxidative damage of cellular macromolecules, toxicity and mutagenicity [1,2]. NAD(P)H:quinone oxidoreductases (NQOs) are cytosolic flavoproteins that compete with P450 reductase and catalyze the reduction of highly reactive quinones and their derivates by complete, two-electron reduction [2]. This results in the formation of relatively stable hydroquinones, often referred to as quinols, and avoids the formation of ROS. While NQO1 uses nicotinamide adenine dinucleotide (phosphate) (NADH or NADPH) as electron donor, NQO2 shows a high preference for dihydronicotinamide riboside (NRH) [3]

Methods

Results

Conclusion