The CoQ-dependent redox reactions in the mitochondria are linked directly or indirectly to oxidative phosphorylation (OXPHOS), in which electrons flow through mitochondrial complexes to generate the proton gradient necessary for ATP synthesis, until they finally reach oxygen to reduce it to water [39], additionally affecting diverse metabolic pathways [41].

To access ETC, the energy of the electron flows clusters the mitochondrial redox reactions into three groups, depending on their redox potential [45]. The more energetic dehydrogenases operate at approximately −280 mV and transfer electrons from metabolites to NAD⁺, reducing it to NADH, and oxidizing the proper metabolite to another with lower potential energy. Within this group, enzymes, for amino acid metabolism, such as 2-oxoadipate dehydrogenase for lysine catabolism and branched-chain dehydrogenases for leucine, isoleucine and valine catabolism; hydroxyacyl-CoA-dehydrogenase for fatty-acid β-oxidation; pyruvate dehydrogenase for carbohydrate catabolism; and the three NAD-dehydrogenases integrated in the Krebs cycle: isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase, and malate dehydrogenase are included. All these dehydrogenases produce NADH to feed mitochondrial complex I, which uses the energy to generate the proton gradient necessary for ATP synthesis and transfers the electrons to ubiquinone reducing it to ubiquinol, which is the substrate for complex III.

The second group of dehydrogenases operate at a lower redox potential of approximately +20 mV. They use FAD, a flavin-adenine dinucleotide that is reduced to FADH₂, and transfer electrons from metabolites directly to ubiquinone, without contribute to the proton gradient generation. This group includes succinate dehydrogenase (complex II), enzymes for amino acid metabolism, such as proline dehydrogenase, dihydroorotate dehydrogenase for pyrimidine nucleotide metabolism, acyl-CoA dehydrogenases for fatty-acid beta oxidation, and glycerol-3-phosphate dehydrogenase, which shuttles the glycolytic electrons from NADH directly to the mitochondrial respiratory chain to regenerate NAD⁺ and avoid the blockage of the glycolysis. All these dehydrogenases use as substrate CoQ producing ubiquinol, which is reoxidized by complex III, using this energy to generate the mitochondrial proton gradient, and finally transferring the electrons to molecules of cytochrome c [41].

The third group of dehydrogenases operate at a very low redox potential of approximately +320 mV. Here, the cytochrome c linked enzymes are included, such as the sulfite dehydrogenase necessary for cysteine catabolism, which oxidizes sulfite to sulfate and reduces cytochrome c. Finally, electrons from cytochrome c go through complex IV, contributing to the proton gradient, until they reach oxygen at +600 mV.

Eleven sites in the ETC that leak electrons to oxygen producing ROS have been associated with substrate oxidation and oxidative phosphorylation in mitochondria [46]. These sites are located inside the oxoacid dehydrogenases that feed electrons to NAD⁺, but higher production has been recorded in proper mitochondrial complexes III, I, and II in the sites where CoQ presents its redox activity [45]. In addition, the rate of ROS production can vary depending on the tissue, showing higher production in brown adipose tissue compared with skeletal muscle, and being heart the organ with lower rates [47]. The type of substrate is also crucial, succinate is the metabolite that causes higher production of ROS, and both fatty acids and amino acids the metabolites that produces the lower levels [46]. Most of the hydrogen peroxide production takes place in complex I, while glycerol-3-phophate, fatty acids and glutamate/malate generate an equal amount in complexes I and III, and inside the proper glycerol-3-phosphate dehydrogenase. ROS is also produced by 2-oxoglutarate dehydrogenase.

Due to the topology of the mitochondria and the presence of a double membrane, these enzymes can generate superoxide either in the intermembrane space or in the matrix, but hydrogen peroxide exclusively in the matrix. The specific site of ROS production is important for redox signaling without generating catastrophic energetic effects [45]. Thus, we can distinguish intramitochondrial redox signaling, in which all targets are located inside mitochondria, and redox signaling from mitochondria to the rest of the cell (retrograde redox signaling). This ROS-dependent signaling process can even affect targets located outside cells. Among the targets affected by mitochondrial ROS are the initiation of hypoxia-inducible factor (HIF) signaling and its effect in gene expression modulation, insulin secretion stimulated by redox signaling due to the metabolism of branched-chain keto acids and fatty acids, retrograde redox signaling that modulates PGC1α during exercise in skeletal muscle, and the redox signaling that affects immune cells [48,49].

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 (G3PDH) that connects glycolysis, OXPHOS, and fatty acid metabolism [52]. CoQ is also reduced by the electron-transport flavoprotein dehydrogenase (ETFDH), an essential enzyme in β-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 dihydroorotate 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 [2Fe–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 ferroptosis 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 ferroptosis caused by mitochondrial dysfunction [39].

Finally, it has been suggested that CoQ inhibits the calcium-dependent opening of the mitochondrial permeability transition pore (PTP) and modulates the mitochondrial uncoupling proteins (UCPs) [40].