Genoxphos

TITLE: Exploring the physiological role of the organization of the mitochondrial respiratory chain complexes.

BACKGROUND: The mitochondrial respiratory chain has a dynamic organization where complexes and supercomplexes coexist.  Recently¹, we have described that complex IV can be in single form, assembled as a dimer or in association with complex III according with the subunit variants. In particular we discovered that the subunit COX7A2 maintains complex IV in single form while the subunit COX7A1 triggers the formation of complex IV dimers, whereas COX7A2L (SCAF1) determines the assembly of supercomplexes III+IV. SCAF1², accordingly to the mouse strain, is present as a long isoform (113 aa) or a short isoform (111 aa) and determines different organization of the mitochondrial respiratory chain that leads to different respiratory performance. The physiological role of the different respiratory chain organizations is still unknown and the impact on metabolism and different pathologies has to be uncovered.   

We created a panel of new mouse models conditional knock out for subunits COX7A2, COX7A1 and SCAF1 in order to study in vivo the role of these subunits and therefore of the different organizations of respiratory chain.

OBJECTIVE: Determine the structure of the respiratory chain complexes and supercomplexes in different tissues of COX7A2, COX7A1 and SCAF1 knock out mice and study the effects of the lack of these subunits on mitochondrial respiration, in response of high fat diet, fasting and exercise.

TECHNIQUES:

in vitro: Isolation and preparation of mitochondria from different tissues; Blue-native page; enzymatic in gel activity assay; western blot assay; respiration assay.

in vivo: insulin resistance and glucose tolerant test ; exercise test.

1.     Cogliati et al. Mechanism of super-assembly of respiratory complexes III and IV. Nature 2016

2.     Lapuente-Brun, et al. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science 2013