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Respiratory supercomplexes: evidence for separate though interconnected compartments of Coenzyme Q10 in mammalian mitochondria.
No full textCoenzyme Q and respiratory supercomplexes: physiological and pathological implications
No full textIt was discovered over 60 years ago that the mitochondrial respiratory chain is constituted of a series of protein complexes imbedded in the inner mitochondrial membrane. Experimental evidence has more recently ascertained that the major respiratory complexes involved in energy conservation are assembled as supramolecular units (supercomplexes, SCs) in stoichiometric ratios. The functional role of SCs is less well defined, and still open to discussion. Several lines of evidence favour the concept that electron transfer from Complex I to Complex III operates by channelling of electrons through Coenzyme Q molecules bound to the SC I1III2IVn, in contrast with the previously accepted hypothesis that the transfer of reducing equivalents from Complex I to Complex III occurs via random diffusion of the Coenzyme Q molecules in the lipid bilayer. On the contrary, electron transfer from Complex III to Complex IV seems to operate, at least in mammals, by random diffusion of cytochrome c molecules between the respiratory complexes even if assembled in SCs. Furthermore, another property provided by the supercomplex assembly is the control of generation of reactive oxygen species by Complex I, that might be important in the regulation of signal transduction from mitochondria. This review discusses physiological and pathological implications of the supercomplex assembly of the respiratory chain
Complex I function in mitochondrial supercomplexes
Full text linkThis review discusses the functional properties of mitochondrial Complex I originating from its presence in an assembled form as a supercomplex comprising Complex III and Complex IV in stoichiometric ratios. In particular several lines of evidence are presented favouring the concept that electron transfer from Complex I to Complex III is operated by channelling of electrons through Coenzyme Q molecules bound to the supercomplex, in contrast with the hypothesis that the transfer of reducing equivalents from Complex I to Complex III occurs via random diffusion of the Coenzyme Q molecules in the lipid bilayer. Furthermore, another property provided by the supercomplex assembly is the control of generation of reactive oxygen species by Complex I. This article is part of a Special Issue entitled Respiratory Complex I, edited by Volker Zickermann and Ulrich Brandt
Two separate though interconneted route underlie NADH and succinate oxidation:kinetic evidence for different functional compartments of Coenzyme Q and/or Complex III.
No full textThe discovery of respiratory supercomplexes (SCs) led to the
proposal that electron transfer between complexes I and III (CI, CIII)
is mediated by channelling of Coenzyme Q (Q), with a kinetic
advantage on the transfer based on random collisions, whereas
electron transfer from CII to CIII obeys to the random collision model.
The evidence for Q channelling, however, is highly controversial [1,
2]. We have approached the problem in bovine heart submitochondrial
particles and in reconstituted proteoliposomes in which CI and
CIII are preserved as SC I1III2. We restricted electron transfer to the Q
area by studying NADH and succinate oxidation by exogenous
cytochrome c (cyt. c) as acceptor, thus avoiding the bottleneck of
endogenous cyt. c. Using this system we found the rates of NADH
and succinate oxidation by cyt. c to be almost completely additive.
The rate obtained by simultaneous addition of NADH and succinate
was much higher than that predicted for a homogeneous Q pool [3],
thus suggesting that NADH and succinate oxidation by cyt. c follow
two different routes. The NADH route presumably operates through
Q channelling in the SC I1III2. However Qpool molecules may
exchange with Qbound in SC, approaching the rates predicted for a
single pool, when the reducing pressure increases by strong CIII
inhibition or when detergents destabilize the SCs. The accessibility of
Qpool to SC I1III2 may be a physiological device to control electron
fluxes from different substrates and implies a dissociation equilibrium
of Qbound with the Q pool, by which the size of the pool
determines saturation of the binding site(s) in the SC. Thus bulk Qpool
has a role also in oxidation of NAD-linked substrates, providing a
rationale for the beneficial effect of exogenous Q supplementation on
mitochondrial bioenergetics.
References
1. JN Blaza et al. Proc Natl Acad Sci USA 111 (2014) 15735-40.
2. G Lenaz et al. BBA Bioenerg. (2016) Epub ahead of print.
3. A Kröger, M Klingenberg. Eur J Biochem. 34 (1973) 358-68
Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology
Full text linkUnder aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-complexes, allows the F1FO-ATP synthase to make ATP from ADP + Pi. Recently mitochondria emerged not only as cell powerhouses, but also as signaling hubs by way of reactive oxygen species (ROS) production. However, when ROS removal systems and/or OXPHOS constituents are defective, the physiological ROS generation can cause ROS imbalance and oxidative stress, which in turn damages cell components. Moreover, the morphology of mitochondria rules cell fate and the formation of the mitochondrial permeability transition pore in the mtIM, which, most likely with the F1FO-ATP synthase contribution, permeabilizes mitochondria and leads to cell death. As the multiple mitochondrial functions are mutually interconnected, changes in protein composition by mutations or in supercomplex assembly and/or in membrane structures often generate a dysfunctional cascade and lead to life-incompatible diseases or severe syndromes. The known structural/functional changes in mitochondrial proteins and structures, which impact mitochondrial bioenergetics because of an impaired or defective energy transduction system, here reviewed, constitute the main biochemical damage in a variety of genetic and age-related diseases
Impact des supercomplexes respiratoires et reprogrammation métabolique des macrophages durant l’immunité antibactérienne
No full textLes macrophages sont des cellules spécialisées de l'immunité innée capables de reconnaître les agents pathogènes et d'induire une réponse immunitaire pour éradiquer la menace. La reprogrammation métabolique est récemment émergée comme une composante majeure des cellules de l'immunité innée après une infection microbienne. Au coeur de ce processus physiologique se trouvent les mitochondries, des organelles clés pour la production d'énergie qui servent également de plateformes de signalisation immunitaire [Sander LE, Garaude J. Mitochondrion (2018)]. L'organisation supramoléculaire dynamique des complexes de la chaîne de transport d'électrons (CTE) des mitochondries en supercomplexes (SCs) peut conférer certains avantages fonctionnels aux mitochondries [Genova ML and Lenaz G. Biochim Biophys Acta (2014)]. Néanmoins, le rôle précis de ces SCs dans les adaptations métaboliques liées à la réponse immunitaire de l'hôte reste à déterminer. Une étude récente indique que suite l'ingestion de bactéries Gram-négatives E. coli vivantes et après engagement des récepteurs de reconnaissance de l'immunité innée, des adaptations structurelles et fonctionnelles du métabolisme mitochondrial sont mise en place dans les macrophages contribuant ainsi à la réponse anti-microbienne [Garaude J et al. Nat Immunol (2016)].Dans mon travail de thèse, j'ai voulu déterminer si la reprogrammation mitochondriale dépend de la nature des bactéries rencontrées et comment cela module l'immunité innée.Nos résultats montrent que la détection des bactéries Gram-négatives et des bactéries Gram-positives par les macrophages régule différemment le taux de consommation d'oxygène mitochondrial (OCR), la synthèse d'ATP mitochondrial et l'activité respiratoire du CII de la chaîne respiratoire mitochondrial. L'analyse métabolomique des macrophages et d’échantillons de plasma de patients atteints de sepsis montre une reprogrammation distincte du cycle du TCA induite par les bactéries Gram-négatives et Gram-positives. Alors que les macrophages traités avec des bactéries Gram-négatives accumulent du fumarate, les macrophages stimulés par des bactéries Gram-positives accumulent du α-cétoglutarate. Ces deux métabolites sont des modulateurs connus de méthyltransférases [Mills EL et al. Cell (2016)], suggérant que la reprogrammation métabolique des mitochondries peut conduire à un contrôle épigénétique de l'expression des gènes dans les macrophages après une infection bactérienne. Nous avons donc étudié si la manipulation pharmacologique du rapport fumarate/α-cétoglutarate et de l'activité SDH/CII module la production de cytokines pro- et anti-inflammatoires in vitro et in vivo. Nos résultats préliminaires indiquent qu'il n'y a pas de différence significative dans la capacité respiratoire mitochondriale et la production d'ATP induite par les inhibiteurs de CII, ce qui suggère des effets compensatoires possibles médiés par les SC et les autres déshydrogénases composant le système de transport d'électrons mitochondrial. D'autres études sont toujours en cours pour élucider l'effet de l'inhibition du CII sur la production de cytokines puisque nous avons observé des niveaux de cytokines opposés in vitro et in vivo.Macrophages are specialized innate immune cells that can recognize pathogens and induce an immune response best suited to eradicate the threat. Metabolic reprogramming has recently emerged as a major feature of innate immune cells following microbial infection. At the core of this physiological process are mitochondria, key organelles for energy production that also serve as immune signalling platforms [Sander LE, Garaude J. Mitochondrion (2018)]. The dynamic supramolecular organization of the mitochondrial electron transport system complexes forming the respiratory supercomplexes (SCs) may confer functional advantages to mitochondria [Genova ML and Lenaz G. Biochim Biophys Acta (2014)]. However, the precise role of SCs in metabolic adaptations in immune host defense remains to be determined. Recent evidence nevertheless indicates that organizational and functional adaptations occur in the ETS of macrophages to allow metabolic plasticity during engulfment of live E. coli [Garaude J et al. Nat Immunol (2016)] and upon engagement of innate immune receptors [Mills EL et al. Cell (2016)]. Furthermore, several groups have demonstrated that the tricarboxylic acid (TCA) cycle (or Krebs cycle) of macrophages stimulated with the Toll-like receptor 4 (TLR4) ligand lipopolysaccharides (LPS) – the main component of Gram-negative cell wall – shows two breakpoints at the isocitrate dehydrogenase (IDH) and at the succinate dehydrogenase (SDH, or Complex II) [Ryan DG and O’Neill LA. Annual Review of Immunology (2020)]. Importantly, previous experiments conducted in Garaude’s laboratory suggested the involvement of Complex II/SDH in macrophages metabolic reprogramming, depending on the microbial stimulus [Garaude J et al. Nat Immunol (2016)].In my thesis work, I have investigated whether mitochondrial reprogramming depends on the nature of the bacteria encountered and how this in turn modulates innate immune outcomes.Our data show that the sensing of Gram-negative bacteria and Gram-positive bacteria by macrophages differentially regulates mitochondrial oxygen consumption rate (OCR), mitochondrial ATP synthesis and respiratory CII activity throughout the time of infection. Metabolomics analysis of bacteria-treated macrophages and plasma samples from patients with sepsis show distinct reprogramming of the TCA cycle induced by Gram-negative and Gram-positive bacteria. While Gram-negative-treated macrophages accumulate fumarate, macrophages stimulated with Gram-positive bacteria accumulate α-ketoglutarate. Those two metabolites are known modulators of histone- and DNA-methyl transferase [Martínez-Reyes & Chandel. Nature Communications (2020)], suggesting that the metabolic reprogramming at the level of mitochondria may also lead to epigenetics control of gene expression in macrophages upon bacterial infection. We thus investigated whether the pharmacological manipulation of fumarate/α-ketoglutarate ratio and SDH/CII activity modulate pro- and anti-inflammatory cytokines production in vitro and in vivo. Our preliminary results indicate that there is no significant difference in mitochondrial respiration capacity and ATP production induced by CII inhibitors, which suggest possible compensatory effects mediated by SCs and the other dehydrogenases composing the mitochondrial electron transport system. Further studies are still ongoing to elucidate the effect of CII inhibition on cytokine production since we observed discrepant results on cytokine levels in vitro and in vivo
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The landscape of rare mitochondrial DNA variants in sudden cardiac death: A potential role for ATP synthase
Full text linkSudden cardiac death (SCD) is a major health concern, which can be the sign of a latent mitochondrial disease. However, mitochondrial DNA (mtDNA) contribution is largely unexplored in SCD at population level. Recently, mtDNA variants have been associated with congenital cardiopathy and higher risk of ischemic heart disease, suggesting them as potential risk factors also in SCD. Therefore, we aimed to define the mtDNA mutational landscape in such phenotype, by sequencing the whole blood mtDNA genome in a pilot cohort of 28 unrelated subjects. Coding variants were prioritized according to their population and haplogroup frequency. Out of 28 patients, 36% were diagnosed with coronary artery disease, 39% with structural defects and 25% with unspecified cardiac disease. The overall frequency of macro-haplogroups followed the distribution in the European population. No known or novel mtDNA pathogenic variants were found. Two rRNA and 8 missense variants were rarer than polymorphisms as they had a frequency lower than 1% in population databases. 5/8 missense variants clustered in ATP synthase genes and 4/8 missense variants were previously detected in patients with suspected mitochondriopathy. We concluded that primary mitochondrial disease is not a major cause of SCD, but rare mtDNA variants may occur (35.7% in our cohort vs 0.65% in the population; p < 0.01), potentially modifying the risk
Macrophage respiratory supercomplexes and metabolic reprogramming upon anti-bacterial immunity
Full text linkMetabolic reprogramming has recently emerged as a major feature of innate immune cells upon bacterial infection. At the core of this physiological process is the mitochondrion, a bioenergetic organelle that also serves as an immune signaling platform. The dynamic supramolecular organization of the mitochondria electron transport system (ETS) complexes forming the respiratory supercomplexes (SCs) may confer functional advantages to mitochondria. However, the precise role of SCs in metabolic adaptations in immune host defense remains to be determined. Indications exist that organizational and functional adaptations occur in the ETS of macrophages to allow metabolic plasticity during engulfment of live Gram-¬negative bacteria (e.g. E. coli). Furthermore, several groups demonstrated that the tricarboxylic acid cycle (or Krebs cycle) of macrophages stimulated with the Toll-like receptor 4 ligand lipopolysaccharides – the main component of Gram- cell wall – shows two breakpoints at the isocitrate dehydrogenase and at the succinate dehydrogenase (SDH/Complex II). Previous experiments suggested the involvement of Complex II in macrophages metabolic reprogramming, depending on the microbial stimulus. In this work we investigated whether mitochondrial reprogramming depends on the nature of the bacteria encountered and how this in turn modulates innate immune outcomes. Our data show that the sensing of Gram- and Gram+ bacteria by macrophages differentially regulates mitochondrial oxygen consumption rate, mitochondrial ATP synthesis and respiratory CII activity throughout the time of infection. Metabolomics analysis of bacteria-treated macrophages show distinct reprogramming of the Krebs cycle induced by Gram- and Gram+ bacteria. We thus investigated whether the pharmacological manipulation of fumarate/α-ketoglutarate ratio and SDH/CII activity modulate pro- and anti-inflammatory cytokines production in vitro and in vivo. Our preliminary results indicate that there is no significant difference in mitochondrial respiration capacity and ATP production induced by CII inhibitors, which suggest possible compensatory effects mediated by SCs and the other dehydrogenases composing the mitochondrial ETS
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