Soutenance de thèse Yoann COMBOT

Equipe

Team IV -  Dyslipidemias and lipotoxicity

Directeur de thèse

Xavier PRIEUR

Rapporteurs

Dr Marthe Moldes, Chargée de recherche, HDR, INSERM, U938 – CRSA, Paris
Dr Cédric Moro, Directeur de recherche, INSERM, U1297 – I2MC, Toulouse

Examinateurs

Pr Bénédicte Gaborit, Professeur d’Université – Praticien Hospitalier, APHM, Marseille
Dr Jennifer Rieusset, Directrice de Recherche, INSERM, U1060 – CarMeN, Lyon 1

Résumé

Berardinelli-Seip congenital lipodystrophy (BSCL) is a disease characterized by an almost total loss of adipose tissue, associated with metabolic complications. In 50% of the cases, BSCL is due to the mutation of the BSCL2 gene, encoding seipin, a protein whose functions are still poorly understood.
In this work, we have shown that BSCL2 patient cells display mitochondrial abnormalities. In vitro studies allowed us to localize seipin in areas of the endoplasmic reticulum (ER) associated with the mitochondrias (called MAMs), in interactions with calcium regulation proteins such as SERCA2, IP3R et VDAC. Seipin is enriched at the MAMs during fasting, while seipin location at ER- lipid droplet contact sites is promoted by lipid loading. The absence of seipin in vitro induces an alteration of mitochondrial calcium as well as the production of Krebs cycle metabolites and ATP. In mice, the adipo-specific deletion of seipin (iATSKO) causes metabolic complications associated with mitochondrial dysfunctions. Furthermore, the number of MAMs is strongly reduced, even during fasting, suggesting the development of metabolic inflexibility. The mitochondria and MAMs fraction of the adipose tissue of iATSKO also exhibits a modification of the lipid composition, characterized in particular by a decrease in the ratio of phospholipids, suggesting an alteration in membrane fluidity. These results suggest that seipin controls calcium and mitochondrial metabolism via its presence in MAMs, and the properties of which are finely regulated in the mature adipocyte.