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Structure and mechanism of respiratory chain molecular machines

Description du projet

Résoudre le mystère de la respiration mitochondriale

Les mitochondries sont considérées comme la centrale électrique des cellules eucaryotes. Elles facilitent la production de la majeure partie de l’énergie nécessaire sous la forme d’ATP. Les enzymes de la chaîne respiratoire sont chargées de convertir en ATP l’énergie libérée par les processus cataboliques au sein de la cellule. Le projet RESPICHAIN, financé par l’UE, se concentrera sur le complexe I, la plus grande enzyme respiratoire, qui se compose de 45 sous-unités. Les chercheurs étudieront le mécanisme de transduction d’énergie effectué par le complexe I et délimiteront sa structure. Ces travaux permettront d’acquérir des connaissances fondamentales en biologie et de mieux comprendre l’étiologie de nombreuses maladies humaines.

Objectif

Eukaryotic life is made possible by energy production in mitochondria, where several large membrane protein complexes of the respiratory chain work in series to produce ATP. The structure and function of these complexes have been intensively studied over decades, but the mechanistic understanding is lacking due to their elaborate architecture. This proposal’s goal is to reveal the mechanism of energy transduction by the least understood of them: complex I, respiratory supercomplexes and transhydrogenase. Complex I is the largest respiratory enzyme, containing up to 45 subunits with a total mass of ~1 MDa. We have determined the first atomic structures of complex I from bacteria and mitochondria. Mammalian complex I usually exists as a supercomplex with complexes III2 and IV: we have determined the first architecture of this ~1.7 MDa physiological “unit” of respiration. The nicotinamide nucleotide transhydrogenase couples proton motive force to mitochondrial redox homeostasis, working in tandem with the respiratory chain. We recently determined the first structure of transhydrogenase but its coupling mechanism remains controversial. Huge conformational changes are envisaged but not yet observed. The mechanism of coupling between spatially separated electron transfer and proton translocation in complex I is also a mystery. It is likewise not known why respiratory complexes are organised into supercomplexes. We will tackle all these questions by an integrative approach, solving the atomic structures of different catalytic states of the complexes by applying the latest cryo-EM methods to these extremely challenging targets. The comparison of structures, complemented by functional and computational analyses, will reveal the mechanistic basis for the function of these molecular machines, solving fundamental questions in biology. As these enzymes are involved in many severe human disorders, the acquired knowledge will also be instrumental to tackle mitochondrial diseases.

Régime de financement

ERC-ADG - Advanced Grant

Institution d’accueil

INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
Contribution nette de l'UE
€ 1 781 133,00
Adresse
Am Campus 1
3400 Klosterneuburg
Autriche

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Région
Ostösterreich Niederösterreich Wiener Umland/Nordteil
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
€ 1 781 133,00

Bénéficiaires (1)