Enriquez 2014 Mol Syndromol

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Enriquez JA, Lenaz G (2014) Coenzyme Q and the respiratory chain: coenzyme Q pool and mitochondrial supercomplexes. Mol Syndromol 5:119-40.

» PMID: 25126045 Open Access

Enriquez JA, Lenaz G (2014) Mol Syndromol

Abstract: Two alternative models of organization of the mitochondrial electron transport chain (mtETC) have been alternatively favored or questioned by the accumulation evidences of different sources, the solid model or the random collision model. Both agree in the number of respiratory complexes (I-IV) that participate in the mtETC, but while the random collision model proposes that Complexes I-IV do not interact physically and that electrons are transferred between them by coenzyme Q and cytochrome c, the solid model proposes that all complexes super-assemble in the so-called respirasome. Recently, the plasticity model has been developed to incorporate the solid and the random collision model as extreme situations of a dynamic organization, allowing super-assembly free movement of the respiratory complexes. In this review, we evaluate the supporting evidences of each model and the implications of the super-assembly in the physiological role of coenzyme Q.

Bioblast editor: Gnaiger E


Communicated by Gnaiger Erich (2021-03-23)
  • Some relevant references are missing, particularly:
  • Rich PR (1984) Electron and proton transfers through quinones and cytochrome bc complexes. Biochim Biophys Acta 768:53-79. - »Bioblast link«
  • Here a harmonization of fundamental terms is attempted (↔):
Enriquez, Lenaz (2014) Rich (1984)
super-assembly in the physiological role of coenzyme Q stoichiometric associations between Complex I and Complex III - in such a case, no 'Q-pool' behaviour was observed
solid model solid state model
random collision model liquid state model
Recently, the plasticity model has been developed to incorporate the solid and the random collision model as extreme situations of a dynamic organization "Solid state" and "liquid state" as extremes of molecular organisation .. The essential figure of interest is N - the number of acceptors within range of a quinol of lifetime t

Selected quotes

  • the enzyme complexes are connected by 2 mobile redox-active molecules, i.e. a lipophilic quinone, designated CoQ or ubiquinone, embedded in the membrane lipid bilayer, and a hydrophilic heme protein, cytochrome c, localized on the external surface of the inner membrane [Green and Tzagoloff, 1966].
  • The inner membrane contains other proteins with electron transfer activity in smaller amounts; among these there are electron transfer flavoproteins (ETF), capable of feeding electrons to the respiratory chain by pathways not involving Complex I and/or NAD, i.e. glycerol-3-phosphate dehydrogenase, ETF-ubiquinone oxidoreductase, dihydroorotate dehydrogenase, choline dehydrogenase, sulfide CoQ reductase (SQR), and proline dehydrogenase besides alternative NADH dehydrogenases in mitochondria from several organisms, especially plants and fungi.
  • The systematic resolution and reconstitution of the 4 respiratory complexes from mitochondria were accomplished by Hatefi et al. [1962a], leading Green and Tzagoloff [1966] to postulate that the overall respiratory activity is the result of both intra-complex electron transfer in solid state between redox components having fixed steric relation and inter-complex electron transfer ensured by rapid diffusion of the mobile components acting as co-substrates, i.e. CoQ and cytochrome c. This proposal was substantially confirmed over the following years, leading to the postulation by Hackenbrock et al. [1986] of the random collision model (RCM) of electron transfer.
  • On the other hand, circumstantial evidence against a random distribution of respiratory complexes came from early investigations reporting isolation of Complex I–III [Hatefi et al., 1962b] and Complex II–III units [Yu et al., 1974], indicating that such units may be preferentially associated in the native membrane.
  • .. knowing the accurate stoichiometry of oxidative phosphorylation complexes, it is plausible that approximately 30 % of total Complex III in bovine mitochondria is not bound to monomeric Complex I. The fraction of Complex IV in free form represents >85 % of total cytochrome oxidase of mitochondria.
  • .. we proposed an integrated model, the plasticity model, for the organization of the mitochondrial electron transport chain. The previous opposed models, solid versus fluid, would be 2 extremely allowed and functional situations of a dynamic range of molecular associations between respiratory complexes [Acín-Peréz et al., 2008].
  • .. the supercomplex organization may not be fixed but be in equilibrium with randomly dispersed complexes in living cells under physiological conditions.
  • The notion of the CoQ pool as the mechanism for integrated electron transfer from dehydrogenases to cytochromes, described by the hyperbolic relationship between the observed rate of electron transfer of the entire respiratory chain and the rate of either reduction or oxidation of CoQ [Kröger and Klingenberg, 1973], has been widely accepted ..
  • The extent to which CoQ is bound to mitochondrial proteins is an important parameter in relation to its function. If we consider bound CoQ in a 1: 1 stoichiometry with the complexes interacting with the quinone (CI, CII, CIII) in mitochondria of bovine heart, we come up to about 0.5 nmol/mg protein that would increase to ca. 0.8 nmol, assuming more than 1 site to be fully occupied in Complex I and Complex III. Since the total CoQ content is >3 nmol/mg [Lenaz, 2001], we must assume that most CoQ (>75 %) is free in the bilayer. A direct study of the amount of CoQ bound to mitochondrial proteins in 5 different mammalian species showed that the protein-bound aliquot ranges between 10–32 % of total CoQ [Lass and Sohal, 1999].
  • The CoQ pool is required for electron transfer from Complex II to Complex III.
  • It must be noted that the ATP-driven reverse electron transfer from succinate to NAD+ occurs in the presence of a high mitochondrial transmembrane proton motive force that, according to Piccoli et al. [2006], might be the physiological signal and at the same time the trigger causing the structural reorganization of the enzymatic complexes of the mitochondrial OXPHOS system. The model hypothesis depicted by Piccoli et al. [2006] from data on cytochrome oxidase was extended to other enzymes of the respiratory chain [Quarato et al., 2011], suggesting that also the I–III supercomplex would dissociate its constituting complexes under high ΔμH+ condition, and this would no longer limit the access to the CoQ binding site in Complex I during reverse electron transfer.
  • Reduction/oxidation of CoQ is critical for energy production, redox balance, pyrimidine synthesis, amino acid and lipid metabolism, and indirectly for apoptosis control and calcium handling.
  • Some reports studying the reduction of CoQ in isolated mitochondria determined that succinate and NADH could reduce a limited and specific fraction of the total CoQ pool [Jørgensen et al., 1985; Lass, 1998].
  • Adaptation to mitochondrial respiratory substrates that generate different proportions of NADH and FAD (as when mitochondria rely on fatty acids rather than glucose during fasting) requires adjustments to the capacity for electron transport via the NADH and FAD routes. Regulated modifications of the proportion of respiratory supercomplexes allow this adaptation [Lapuente-Brun et al., 2013].
  • The primary proposed functional consequence of supercomplex assemblies in the respiratory chain was substrate channeling or enhanced catalysis in inter-complex electron transfer. Substrate channeling is the direct transfer of an intermediate between the active sites of 2 enzymes catalyzing consecutive reactions [Ovádi, 1991]; in the case of electron transfer this means direct transfer of electrons between 2 consecutive enzymes by successive reduction and re-oxidation of the intermediate without its diffusion in the bulk medium.
  • Quarato et al. [2011] showed that the control coefficients were high under conditions of low membrane potential (state 3 or uncoupling) but much lower at membrane potential exceeding 180 mV (state 4), suggesting that the supercomplexes may be in a dynamic equilibrium with the isolated complexes depending on the energetic state of the membrane, thus supporting a previous observation from the same laboratory [Piccoli et al., 2006]. The existence of a dynamic equilibrium of the respiratory complexes from an isolated form to supercomplex association supports the plasticity model [Acín-Peréz et al., 2008].
  • Complex I is almost totally associated in a supercomplex with Complex III, with electron channeling of bound CoQ in the boundary between the 2 complexes. The CoQ pool is, however, directly required for electron transfer from Complex II to Complex III. On the other hand, the finding that Complex I is almost totally associated in a supercomplex with Complex III seems to exclude a role for the CoQ pool in physiological electron transfer between these 2 complexes. Surprisingly, strong evidence exists that NADH-cytochrome c reductase activity follows saturation kinetics with respect to CoQ.
  • Direct titrations of CoQ-depleted mitochondria reconstituted with different CoQ supplements yielded a Km of NADH oxidation for Qt in the range of 2–5 nmol/mg mitochondrial protein [Estornell et al., 1992], corresponding to a Qt concentration of 4–10 mM in the lipid bilayer.
  • To be in agreement with the experimental observation obtained by metabolic flux analysis, this proposition requires that the dissociation rate constants (koff) of bound CoQ be considerably slower than the rates of inter-complex electron transfer via the same bound quinone molecules [Lenaz and Genova, 2010; Genova and Lenaz, 2011]. The high apparent Km for CoQ10 in NADH oxidation is in line with this postulation.
  • It is likely that the function of the large amount of ubiquinone in the natural membrane may be, therefore, to maintain the ubiquinone-10 content in the supercomplex unit when it is formed.

Cited by

  • Komlodi et al (2021) Simultaneous measurement of respiration and redox state of the Coenzyme Q pool in mitochondrial preparations. Bioenerg Commun 2021.3 doi:10.26124/bec:2021-0003

Labels: MiParea: Respiration 

Stress:Oxidative stress;RONS 

Preparation: Isolated mitochondria 

Regulation: Cyt c, Flux control, mt-Membrane potential, pH, Redox state, Q-junction effect 

Pathway: N, S, Gp, CIV 

MitoFit 2021 CoQ