Mitochondrial ATP synthase: architecture, function and pathology

Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F1, situated in the mitochondrial matrix, and Fo, located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V. The role of complex V di-and oligomerization and its relation with mitochondrial morphology is discussed. Finally, pathology related to complex V deficiency and current therapeutic strategies are highlighted. Despite the huge progress in this research field over the past decades, questions remain to be answered regarding the structure of subunits, the function of the rotary nanomotor at a molecular level, and the human complex V assembly process. The elucidation of more nuclear genetic defects will guide physio(patho)logical studies, paving the way for future therapeutic interventions

Regulation of the F1F0-ATP Synthase Rotary Nanomotor in its Monomeric-Bacterial and Dimeric-Mitochondrial Forms

The F1F0-adenosine triphosphate (ATP) synthase rotational motor synthesizes most of the ATP required for living from adenosine diphosphate, Pi, and a proton electrochemical gradient across energy-transducing membranes of bacteria, chloroplasts, and mitochondria. However, as a reversible nanomotor, it also hydrolyzes ATP during de-energized conditions in all energy-transducing systems. Thus, different subunits and mechanisms have emerged in nature to control the intrinsic rotation of the enzyme to favor the ATP synthase activity over its opposite and commonly wasteful ATPase turnover. Recent advances in the structural analysis of the bacterial and mitochondrial ATP synthases are summarized to review the distribution and mechanism of the subunits that are part of the central rotor and regulate its gyration. In eubacteria, the ε subunit works as a ratchet to favor the rotation of the central stalk in the ATP synthase direction by extending and contracting two α-helixes of its C-terminal side and also by binding ATP with low affinity in thermophilic bacteria. On the other hand, in bovine heart mitochondria, the so-called inhibitor protein (IF1) interferes with the intrinsic rotational mechanism of the central γ subunit and with the opening and closing of the catalytic β-subunits to inhibit its ATPase activity. Besides its inhibitory role, the IF1 protein also promotes the dimerization of the bovine and rat mitochondrial enzymes, albeit it is not essential for dimerization of the yeast F1F0 mitochondrial complex. High-resolution electron microscopy of the dimeric enzyme in its bovine and yeast forms shows a conical shape that is compatible with the role of the ATP synthase dimer in the formation of tubular the cristae membrane of mitochondria after further oligomerization. Dimerization of the mitochondrial ATP synthase diminishes the rotational drag of the central rotor that would decrease the coupling efficiency between rotation of the central stalk and ATP synthesis taking place at the F1 portion. In addition, F1F0 dimerization and its further oligomerization also increase the stability of the enzyme to natural or experimentally induced destabilizing conditions

Molecular Structure, Biosynthesis, and Distribution of Coenzyme Q

Coenzyme Q is a very old molecule in evolutionary terms that has accumulated numerous functions in the cellular metabolism beyond its primordial function, the electron transport. In all organisms, coenzyme Q maintains a highly conserved structure allowing a localization inside cell membranes in a hydrophobic environment thanks to having an isoprenoid tail, and at the same time allows the polar ring benzene to interact with acceptors and electron donors. Coenzyme Q deficiency constitutes a group of mitochondrial diseases. Affected patients suffer mainly a decrease in energy production that induces dysfunctions in most organs and body systems. Current therapeutic alternatives are based on increasing coenzyme Q levels either through induction of endogenous mechanisms or exogenous supplementation. This chapter includes both aspects, the mechanisms associated with the coenzyme Q supplementation and the regulatory mechanisms of coenzyme Q biosynthesis. In terms of synthesis, the structure of coenzyme Q is complicated since it requires the participation of two well-differentiated pathways that must be carefully regulated. The synthesis is carried out through the participation of a multienzyme complex located in the inner mitochondrial membrane and controlled by different levels of regulation that at this time are not well-known