# Coenzyme Q at the Hinge of Health and Metabolic Diseases
## 3 CoQ as Metabolic Integrative Factor for Cellular Homeostasis
### Mitochondrial Redox Reactions
#### 3.1.3 Mitochondrial CoQ Is Essential for Many Different Metabolic Processes  
In addition to its known activity as a redox carrier among complexes I, II, and III of the ETC, CoQ also receives electrons from many different dehydrogenases [41; 50; 51]. CoQ receives electrons from mitochondrial glycerol-3-phosphate dehydrogenase (G3 PDH) that connects glycolysis, OXPHOS, and fatty acid metabolism [52]. CoQ is also reduced by the electron-transport flavoprotein dehydrogenase (ETFDH), an essential enzyme in \(\beta\)-oxidation of fatty acids and in the oxidation of branched amino acids [53]. The capacity as an electron acceptor of CoQ is also essential for the activity of proline dehydrogenase (PROD), involved in glyoxylate metabolism [54], and sulphide-quinone oxidoreductase (SQR) that participates in sulphide detoxification [55], an important regulator of many cellular processes [56; 57]. Further, CoQ is also reduced by choline dehydrogenase (CHDH) [58], from choline to glycine conversion, and dihydrororotate dehydrogenase (DHODH), from dihydro-orotate to orotate transformation, which is involved in pyridine nucleotide synthesis [59]. Further, CoQ also participates in the dissipation of energy from the ETC by the dissemination of the proton gradient as heat. CoQ associates to uncoupling proteins localized in the IMM playing in its regulation [60]. Moreover, it has recently been shown that the oxidation of ubiquinol by complex III of the ETC is an obligatory reaction to maintain tumor growth [61]. Another important aspect of the essential participation of CoQ in mitochondrial physiology is its role as a structural element in complexes I and III in the ETC [62; 63]. In fact, CoQ is essential for the maintenance of the structure of complex III since the supplementation of yeast with CoQ restores the assembly of complex III in CoQ-deficient strains [64], and CoQ is also involved in complex I stability [65]. Interestingly, the deterioration of complexes I and III has been associated with the progression of different neurodegenerative diseases [66; 67]. Further, defects of complexes downstream of the CoQ site end in the accumulation of ubiquinol in ETC that destabilizes complex I by ROS production, generating a vicious cycle [65]. CoQ is also a component of respirasome [68; 69], and also participates in the assembly and the dynamics of supercomplexes [70]. Recently, it has been indicated that OPA1, a regulator of the fusion of the mitochondrial outer membrane, mediates the regulation of complex IV activity through a CoQ-dependent procedure [71]. Interestingly, a pool of CoQ is associated with complex I + III + IV supercomplexes, whereas free CoQ is dedicated to complex II-dependent respiratory chain activity [72; 73; 74]. This is very important as supercomplexes are associated with a balanced ETC chain activity and point to the regulatory role of CoQ in their assembly dynamics [70; 75; 76]. CoQ is also importantly implicated in the dynamics of the assembly and stability of these supercomplexes involved in mitochondrial efficiency that, when altered, induce mitochondrial dysfunction-mediated metabolic diseases and aging [77; 78]. Recently, another key function of CoQ in mitochondria has been found in the outer membrane [79]. MitoNEET, also known as CDGS1 iron sulfur domain 1 (CISD1) protein, is a redox-active and pH-sensing protein that regulates energy metabolism, iron homeostasis, and ROS in mitochondria. MitoNEET interacts with reduced flavin mononucleotide (FMNH2) that reduces mitoNEET sulfoferric [2 Fe-2S] clusters, which are oxidized back with CoQ being the most efficient electron acceptor [39; 57]. As one of the proteins repaired by MitoNEET is the iron-master regulator IRP-1, which limits iron access to mitochondria to protect against ferprotosis in high ROS production, CoQ can be considered as an important redox-sensing factor in the adaptive response against oxidative injury, and a key component in the prevention of ferprotosis caused by mitochondrial dysfunction [39].