Structural Studies of ACAD9 and mitochondrial complex assembly factors to investigate their role in neurodegeneration

PhD Defense
Start Date
27-02-2019 14:00
End Date
27-02-2019 16:00
Auditorium, Central Building
Speaker's name
Romain Bouverot
Speaker's institute
ESRF Grenoble, France
Contact name
Claudine Roméro
Host name
Montserrat Soler Lopez & Gordon Leonard
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Mitochondria are responsible for bioenergetics, particularly critical in the brain, since neurons are extremely energy demanding. Mitochondria generate the energetic potential through the respiratory chain, which is composed of four protein complexes (I to IV) embedded into the mitochondrial inner membrane. Complex I (CI) is composed of 45 protein subunits and initiates the system. The integration of these subunits and the insertion of cofactors into the nascent complex requires the help of assembly factors, which may act as chaperones that stabilize the intermediate assemblies and help to dock them to build the complete enzyme. Defects in the assembly of CI severally impair energy production and are implicated in several mitochondrial disorders, including neurodegenerative diseases.

Recently, the CI assembly factors NDUFAF1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 1), ACAD9 (Acyl-CoA dehydrogenase 9), ECSIT (Evolutionarily conserved signaling intermediate in Toll pathway) were proposed to form the so-called Mitochondrial Complex I Assembly (MCIA) complex. However, the composition and function of the MCIA complex are unknown, which precludes a proper understanding of the structural and mechanistic bases for building-up CI assembly intermediates.

This thesis pursues the characterisation of the MCIA components, mapping their interactions and characterising their structures using a combination of biophysical and biochemical approaches in order to elucidate the molecular mechanisms underlying the MCIA complex formation and assembly function.

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