The multiple roles of coenzyme Q in cellular homeostasis and their relevance for the pathogenesis of coenzyme Q deficiency

Coenzyme Q at the Hinge of Health and Metabolic Diseases

“…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 ].…”

“…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 ].…”

“…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 ].…”

“…CoQ in plasma membrane contributes to prevent ferroptosis, as substrate of ferroptosis suppressor protein 1 (FSP1), acting in association to the glutathione-dependent lipid hydroperoxidase 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 ].…”

Animal Models of Coenzyme Q Deficiency: Mechanistic and Translational Learnings

“…Some of the biosynthetic proteins are assembled into a high molecular mass complex, named complex Q, with the objective of improving the catalytic efficiency of the CoQ biosynthetic pathway and minimizing the escape of intermediates [4,29,37] (Figure 2b). The benzoquinone ring of CoQ can be found in its completely oxidized form (ubiquinone, CoQ), in the semireduced form (ubisemiquinone, CoQH•), and in the completely reduced form (ubiquinol, CoQH 2 ) after receiving two electrons [1,4] (Figure 2c). CoQ levels can be severely reduced in a group of mitochondrial diseases named CoQ deficiencies, which are clinically and genetically heterogeneous disorders.…”