# Coenzyme Q at the Hinge of Health and Metabolic Diseases
## 3 CoQ as Metabolic Integrative Factor for Cellular Homeostasis
### Extramitochondrial Redox Reactions  
Since the discovery that extramitochondrial ubiquinol possesses antioxidant functions, efforts have been made to characterize the physiological enzyme reduction systems. It has been widely described that CoQ and vitamin E inhibit lipid peroxidation by scavenging lipid peroxyl radicals, and that CoQ directly scavenges the perferryl radical, thereby preventing the initiation of lipid peroxidation [57; 80].  
These important functions require continuous regeneration of ubiququinol from the oxidized ubiquinone and different quinone reductases have been proposed. In this way, the cytosolic enzymes that reduce extramitochondrial ubiquinone can be grouped depending on their dependence on NADPH and NADH and if they have flavin adenine dinucleotide (FAD) as prosthetic group [80]. The highest rate of extramitochondrial ubiquinone reduction described is accomplished by flavoenzymes belonging to a unique family of pyridine nucleotide oxidoreductaseases, such as lipoamide dehydrogenase (LipDH), mammalian thioredoxin reductase (TrxR-1), and glutathione reductase (GR) [80]. LipDH reduces CoQ with either NADH or NADPH, works at acidic pH, and its activity depends on the presence of zinc. TrxR-1 is a selenoenzyme with very broad substrate specificity that has an optimal physiological pH of 7.5 and uses either NADPH or NADH, being the most efficient ubiquinone reductase so far tested. GR is a flavoenzyme, the activity of which is also stimulated by zinc, and has an acidic pH.  
On the other hand, NAD(P)H:quinone acceptor oxidoreductasease1 (NQO1) plays a central role in the processes of stress adaptation, including oxidative stress [42]. NQO1 and cytochrome b\({}_{5}\) reductase (CYTB5R3) regulate the stress adaptation response as a central component of the transplasma membrane redox system that is responsible for preventing lipid peroxidation by reducing oxidized antioxidants, such as vitamins E and C, and the proper CoQ [81; 82]. An overexpression of these enzymes in mice improved health- and life-span by modulating lipid-mediated respiration [83; 84; 85]. CoQ is also involved in alterations in the redox environment by receiving highly energized electrons from NAD(P)H, and possibly in the local regulation of NAD(P)H-dependent enzymes, such as sirtuins acting as metabolic switch [1; 86].  
CoQ in plasma membrane contributes to prevent ferprotosis, as substrate of ferprotosis suppressor protein 1 (FSP1), acting in association to the glutathione-dependent lipid hydroper oxidase glutathione peroxidase 4 (GPX4) [87; 88]. The relevant extramitochondrial redox reactions that depend on CoQ, which are integrated with other pathways, are essential to regulate cellular homeostasis and metabolism [57].  
CoQ also plays an key antioxidant role in the prevention of oxidative damage in plasma cholesterol lipoproteins, essentially in low-density lipoproteins (LDLs) [89]. This role has been essentially considered in the prevention of, and protection against, cardiovascular diseases and atherogenesis [4; 90]. Interestingly, a NADH-dependent reductase able to reduce LDL-associated CoQ has been found in the outer side of the plasma membrane of hepatocytes [91], possibly indicating a mechanism to maintain the redox cycle of CoQ in plasma. The importance of this enzyme in the maintenance of ubiquinol in plasma in aging and metabolic diseases is under study.