282 research outputs found
The flitting of electrons in complex I: A stochastic approach
AbstractA stochastic approach based on the Gillespie algorithm is particularly well adapted to describe the time course of the redox reactions that occur inside the respiratory chain complexes because they involve the motion of single electrons between the individual unique redox centres of a given complex. We use this approach to describe the molecular functioning of the peripheral arm of complex I based on its known crystallographic structure and the rate constants of electron tunnelling derived from the Moser and Dutton phenomenological equations. There are several possible electrons pathways but we show that most of them take the route defined by the successive sites and redox centres: NADH+ site – FMN – N3 – N1b – N4 – N5 – N6a – N6b – N2 – Q site. However, the electrons do not go directly from NADH towards the ubiquinone molecule. They frequently jump back and forth between neighbouring redox centres with the result that the net flux of electrons through complex I (i.e. net number of electrons reducing a ubiquinone) is far smaller than the number of redox reactions which actually occur. While most of the redox centres are reduced in our simulations the degree of reduction can vary according to the individual midpoint potentials. The high turnover number observed in our simulation seems to indicate that, in the whole complex I, one or several slower step(s) follow(s) the redox reactions involved in the peripheral arm. It also appears that the residence time of FMNH• and SQ• (possible producers of ROS) is low (around 4% and between 1.6% and 5% respectively according to the values of the midpoint potentials). We did not find any evidence for a role of N7 which remains mainly reduced in our simulations. The role of N1a is complex and depends upon its midpoint potential. In all cases its presence slightly decreases the life time of the flavosemiquinone species. These simulations demonstrate the interest of this type of model which links the molecular physico-chemistry of the individual redox reactions to the more global level of the reaction, as is observed experimentally
Quesnay and the analysis of the surplus in an agrarian capitalist economy
In order to discuss the ‘rational foundation’ of certain aspects of Quesnay´s theory we use a simple formalization of the necessary connections between assumptions about the techniques in use, the distribution of income between the classes and sectors, the system of relative prices. We argue that Quesnay´s system was a truly capitalist agrarian economy and that he was indeed a pioneer of the classical political economy/surplus approach to economics as identified first by Marx, Sraffa and Garegnani, the physical surplus of grains being the necessary basis for his analysis of the distribution and relative prices
Simulation of mitochondrial metabolism using multi-agents system
Metabolic pathways describe chains of enzymatic reactions. Their modelling is
a key point to understand living systems. An enzymatic reaction is an
interaction between one or several metabolites (substrates) and an enzyme
(simple protein or enzymatic complex build of several subunits). In our
Mitochondria in Silico Project, MitoScop, we study the metabolism of the
mitochondria, an intra-cellular organelle. Many ordinary differential equation
models are available in the literature. They well fit experimental results on
flux values inside the metabolic pathways, but many parameters are dicult
to transcribe with such models: localization of enzymes, rules about the
reactions scheduler, etc Moreover, a model of a significant part of
mitochondrial metabolism could become very complex and contain more than 50
equations. In this context, the multi-agents systems appear as an alternative
to model the metabolic pathways. Firstly, we have looked after membrane design.
The mitochondria is a particular case because the inner mitochondrial space, ie
matricial space, is delimited by two membranes: the inner and the outer one. In
addition to matricial enzymes, other enzymes are located inside the membranes
or in the inter-membrane space. Analysis of mitochondrial metabolism must take
into account this kind of architecture
Quesnay and the analysis of the surplus in an agrarian capitalist economy
In order to discuss the ‘rational foundation’ of certain aspects of Quesnay´s theory we use a simple formalization of the necessary connections between assumptions about the techniques in use, the distribution of income between the classes and sectors, the system of relative prices. We argue that Quesnay´s system was a truly capitalist agrarian economy and that he was indeed a pioneer of the classical political economy/surplus approach to economics as identified first by Marx, Sraffa and Garegnani, the physical surplus of grains being the necessary basis for his analysis of the distribution and relative prices
Theoretical studies on the control of oxidative phosphorylation in muscle mitochondria: application to mitochondrial deficiencies
Modélisation de la Chaîne Respiratoire et de la Phosphorylation Oxydative
Mitochondria are cell organelles which play an essential role in the cell energy supply providing the universal high energetic molecule ATP which is used in numerous energy consuming processes. The core of the ATP production, oxidative phosphorylation (OXPHOS) consists of four enzyme complexes (respiratory chain) which establish, driven by redox reactions, a proton gradient over the inner mitochondrial membrane. The ATP-synthase uses this electrochemical gradient to phosphorylate ADP to ATP. Dysfunctioning of an OXPHOS complex can have severe consequences for the energy metabolism and cause rare but incurable dysfunctions in particular tissues with a high energy demand such as brain, heart, kidney and skeleton muscle. Moreover mitochondria are linked to widespread diseases like diabetes, cancer, Alzheimer and Parkinson. Further, reactive oxygen species which are a by-product of the respiratory chain, are supposed to play a crucial role in aging. The aim of this work is to provide a realistic model of OXPHOS which shall help understanding and predicting the interactions within the OXPHOS and how a local defect (enzyme deficiency or modification) is expressed globally in mitochondrial oxygen consumption and ATP synthesis. Therefore we chose a bottom-up approach. In a first step different types of rate equations were analyzed regarding their ability to describe the steady state kinetics of the isolated respiratory chain complexes in the absence of the proton gradient. Here Michaelis-Menten like rate equations were revealed to be appropriate for describing their behavior over a wide range of substrate and product concentrations. For the validation of the equations and the parameter estimation we have performed kinetic measurements on bovine heart submitochondrial particles. The next step consisted in the incorporation of the proton gradient into the rate equations, distributing its influence among the kinetic parameters such that reasonable rates were obtained in the range of physiological electrochemical potential differences. In the third step, these new individual kinetic rate expressions for the OXPHOS complexes were integrated in a global model of oxidative phosphorylation. The new model could fit interrelated data of oxygen consumption, the transmembrane potential and the redox state of electron carriers. Furthermore, flux inhibitor titration curves can be well reproduced, which validates its global responses to local effects. This model may be of great help to understand the increasingly recognized role of mitochondria in many cell processes and diseases as illustrated by some simulations proposed in this work.Les mitochondries sont l usine à énergie de la cellule. Elles synthétisent l ATP à partir d une succession de réactions d oxydo-réduction catalysées par quatre complexes respiratoires qui forment la chaîne respiratoire. Avec la machinerie de synthèse d ATP l ensemble constitue les oxydations phosphorylantes (OXPHOS). Le but de ce travail est de bâtir un modèle des OXPHOS basé sur des équations de vitesse simples mais thermodynamiquement correctes, représentant l activité des complexes de la chaîne respiratoire (équations de type Michaelis- Menten). Les paramètres cinétiques de ces équations sont identifiés en utilisant les cinétiques expérimentales de ces complexes respiratoires réalisées en absence de gradient de proton. La phase la plus délicate de ce travail a résidé dans l introduction du gradient de protons dans ces équations. Nous avons trouvé que la meilleure manière était de distribuer l effet du gradient de proton sous forme d une loi exponentielle sur l ensemble des paramètres, Vmax et Km pour les substrats et les produits. De cette manière, j ai montré qu il était possible de représenter les variations d oxygène, de et de pH trouvés dans la littérature. De plus, contrairement aux autres modèles, il fut possible de simuler les courbes de seuil observées expérimentalement lors de la titration du flux de respiration par l inhibiteur d un complexe respiratoire donné.Ce modèle pourra présenter un très grand intérêt pour comprendre le rôle de mieux en mieux reconnu des mitochondries dans de nombreux processus cellulaires, tels que la production d espèces réactives de l oxygène, le vieillissement, le diabète, le cancer, les pathologies mitochondriales etc. comme l illustrent un certain nombre de prédictions présentées dans ce travail.BORDEAUX2-Bib. électronique (335229905) / SudocSudocFranceF
- …