Functions of NQO1 in Cellular Protection and CoQ10 Metabolism and its Potential Role as a Redox Sensitive Molecular Switch

Abstract

NQO1 is one of the two major quinone reductases in mammalian systems. It is highly inducible and plays multiple roles in cellular adaptation to stress. A prevalent polymorphic form of NQO1 results in an absence of NQO1 protein and activity so it is important to elucidate the specific cellular functions of NQO1. Established roles of NQO1 include its ability to prevent certain quinones from one electron redox cycling but its role in quinone detoxification is dependent on the redox stability of the hydroquinone generated by two-electron reduction. Other documented roles of NQO1 include its ability to function as a component of the plasma membrane redox system generating antioxidant forms of ubiquinone and vitamin E and at high levels, as a direct superoxide reductase. Emerging roles of NQO1 include its function as an efficient intracellular generator of NAD⁺ for enzymes including PARP and sirtuins which has gained particular attention with respect to metabolic syndrome. NQO1 interacts with a growing list of proteins, including intrinsically disordered proteins, protecting them from 20S proteasomal degradation. The interactions of NQO1 also extend to mRNA. Recent identification of NQO1 as a mRNA binding protein have been investigated in more detail using SERPIN1A1 (which encodes the serine protease inhibitor α-1-antitrypsin) as a target mRNA and indicate a role of NQO1 in control of translation of α-1-antitrypsin, an important modulator of COPD and obesity related metabolic syndrome. NQO1 undergoes structural changes and alterations in its ability to bind other proteins as a result of the cellular reduced/oxidized pyridine nucleotide ratio. This suggests NQO1 may act as a cellular redox switch potentially altering its interactions with other proteins and mRNA as a result of the prevailing redox environment.

Keywords: coenzyme Q; polymorphism; quinone reductases; quinones; single nucleotide; superoxide; vitamin E.

Figure 1

The properties of the hydroquinone determine whether reduction by NQO1 leads to detoxification or toxicity.

Figure 2

Role of NQO1 in generating antioxidant forms of ubiquinone and α-tocopherol in the plasma membrane redox system (adapted from Hyun et al., 2006).

Figure 3

Potential role for NQO1 in generating NAD⁺ for utilization by sirtuins and PARP.

Figure 4

The diverse functions of NQO1.

Figure 5

NQO1 as a redox switch. A schematic diagram of NQO1 in the role of a redox responsive molecular switch. The conformation of NQO1 changes in response to levels of reduced pyridine nucleotides. Under normal condition adequate levels of NAD(P)H keep NQO1 in the reduced conformation (FADH₂) but when NAD(P)H levels fall, NQO1 adopts an oxidized conformation (FAD) exposing its C-terminus domains (-COOH). The change in conformation induced in NQO1 in response to the NAD(P)⁺ / NAD(P)H redox balance alters the binding of either target proteins or RNA to NQO1. X and Y designate NQO1 binding proteins or RNA molecules and it is possible that depending upon the individual target binding to NQO1 may be either increased or reduced by changes in the intracellular NAD(P)⁺ / NAD(P)H ratios.