Coenzyme Q (CoQ) is a lipidic compound widely distributed in nature with crucial functions in metabolism, protection against oxidative damage and ferroptosis, and other processes. CoQ biosynthesis is a conserved and complex pathway involving several proteins. COQ2 is a member of the UbiA family of transmembrane prenyltransferases that catalyzes the condensation of the head and tail precursors of CoQ, a key step in the process because its product is the first intermediate that will be modified in the head by the next component of the synthesis process. Mutations in this protein have been linked to primary CoQ deficiency in humans, a rare disease predominantly affecting organs with a high energy demand. The reaction catalyzed by COQ2 and its mechanism are still unknown. Here we aimed at clarifying COQ2 reaction by exploring possible substrate binding sites using a strategy based on homology, comprising the identification of ligand-bound homologs with solved structures available in the Protein Data Bank (PDB) and their subsequent structural superposition to the AlphaFold predicted model for COQ2. The results highlight some residues located on the central cavity or the matrix loops that may be involved in substrate interaction, some of them mutated in primary CoQ deficiency patients. Furthermore, we analyze the structural modifications introduced by the pathogenic mutations found in humans. These findings shed new light on the understanding of COQ2 function and, thus, CoQ biosynthesis and pathogenicity of primary CoQ deficiency.

Coenzyme CoQ10 (CoQ10) is an endogenous lipid-soluble antioxidant that effectively protects lipids, proteins and DNA from oxidation due to its ability to undergo redox transitions between oxidized and reduced forms. Various oxidative stress-associated infectious and somatic diseases have been observed to disrupt the balance of CoQ10 concentration in tissues. As a high molecular weight polar lipophilic compound, CoQ10 exhibits very limited oral bioavailability, which restrains its therapeutic potential. Nevertheless, numerous studies have confirmed the clinical efficacy of CoQ10 therapy through the oral administration of high doses over extended time periods. Experimental studies have demonstrated that in emergency situations, intravenous administration of both oxidized and reduced forms CoQ10 leads to a rapid increase in its concentration in organ tissues, offering protection in ischemic conditions for organ tissues. This suggests that the cardio- and neuroprotective efficacy of intravenously administered CoQ10 forms could present new opportunities in treating acute ischemic conditions. Based on these findings, the review provides reasoning supporting further research and implementation of CoQ10 dosage forms for intravenous administration in emergency situations into clinical practice.

The single set of electron transporters of the cardiac mitochondrial respiratory chain is organized into three separate supercomplexes. Two of them contain complex I, a dimer of complex III, and two dimers of complex IV. The third supercomplex contains a dimer of complex III and two dimers of complex IV. We also considered two important discoveries. First, the enzymes of β-oxidation of fatty acids are physically associated with respirasome. Second, β-oxidation of fatty acids creates the highest level of QH2 and reverses the flow of electrons from QH2 through complex II, reducing fumarate to succinate. We argue that the respirasome is uniquely adapted for the β-oxidation of fatty acids. The acyl-CoA dehydrogenase complex reduces the membrane’s pool of ubiquinone to QH2, which is instantly oxidized by the 2complex III-4complex IV supercomplex, generating high energization of mitochondria and reversing the electrons flow through the complex II, which reverses the electrons flow through the complex I increasing the NADH/NAD+ ratio in the matrix. The mitochondrial nicotinamide nucleotide transhydrogenase catalyzes a hydride (H-, a proton plus two electrons) transfer across the inner mitochondrial membrane, reducing the cytosolic pool of NADP(H), thus providing the heart with ATP for muscle contraction and energy and reducing equivalents for the housekeeping processes.