On the role of ubiquinone in the proton translocation mechanism of respiratory complex I

Abstract

Complex I converts oxidoreduction energy into a proton electrochemical gradient across the inner mitochondrial or bacterial cell membrane. This gradient is the primary source of energy for aerobic synthesis of ATP. Oxidation of reduced nicotinamide adenine dinucleotide (NADH) by ubiquinone (Q) yields NAD + and ubiquinol (QH 2 ), which is tightly coupled to translocation of four protons from the negatively to the positively charged side of the membrane. Electrons from NADH oxidation reach the iron-sulfur centre N2 positioned near the bottom of a tunnel that extends circa 30 Å from the membrane domain into the hydrophilic domain of the complex. The tunnel is occupied by ubiquinone, which can take a distal position near the N2 centre or proximal positions closer to the membrane. Here, we review important structural, kinetic and thermodynamic properties of ubiquinone that define its role in complex I function. We suggest that this function exceeds that of a mere substrate or electron acceptor and propose that ubiquinone may be the redox element of complex I coupling electron transfer to proton translocation.

Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy

“…Studies of the structure and kinetics of the electron transfer chain performed with X-ray diffraction and cryo-EM have confirmed that the ND1 channel is already a very tight fit for CoQ10 ( 27 ), as well as indicating two stable binding positions for CoQ10 within the tunnel, with perhaps only one close enough to N2 for effective e-transfer ( 28 ). Further, refined investigations with cryo-EM and X-ray crystallography performed on the mutant complex with CoQ10 will possibly provide supporting evidence of the distance of the CoQ10 head group to the N2 FeS cluster.…”

Structural basis of respiratory complexes adaptation to cold temperatures

“…15 Å from the N2 FeS cluster, which will drop the electron transfer rate to hundreds of microseconds (Figure S8E, Tables S5-S7). The latter site most likely prevents the reverse electron transfer(37–39), and thus enhances the rate of forward reaction of complex I. Alternatively, it has been suggested based on structural data that more than one Q molecules can occupy the Q tunnel(32) and complex I may function with the involvement of two Q molecules with a redox reaction between them(40). To further probe the electron distribution for each complex type in this alternative experimental setting, we created additional QM/MM setups with two quinone molecules modeled in the Q tunnel (see Materials and Methods).…”

“…Alternatively, it has been suggested based on structural data that more than one Q molecules can occupy the Q tunnel (32) and complex I may function with the involvement of two Q molecules with a redox reaction between them (40). To further probe the electron distribution for each complex type in this alternative experimental setting, we created additional QM/MM setups with two quinone molecules modeled in the Q tunnel (see Materials and Methods).…”

The Ubiquinone-Ubiquinol Redox Cycle and Its Clinical Consequences: An Overview

“…Complex I receives two electrons from NADH (generated in the Krebs cycle and the beta-oxidation pathway) via a flavin mononucleotide (FMN) and transfers them along a chain of seven iron–sulphur centres to the reduction site where CoQ10 is reduced to ubiquinol. At the same time, this reaction is coupled with the pumping of four protons across the inner mitochondrial membrane and into the intermembrane space; thus, Complex I is a major contributor to the proton motive force driving ATP synthesis (Wikstrom et al, 2023) [ 3 ]. Complex II catalyses the oxidation of succinate to fumarate in the Krebs cycle, with the concomitant transfer of electrons from succinate to ubiquinone to form ubiquinol.…”