Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1

Marion Seillier (1) , Laurent Pouyet (1) , Prudence N’guessan (1) , Marie Nollet (1) , Florence Capo (1) , Fabienne Guillaumond (1) , Laure Peyta (2) , Jean-François Dumas (2) , Annie Varrault (3) , Gyslaine Bertrand (3) , Stéphanie Bonnafous (4, 5) , Albert Tran (5, 4) , Gargi Meur (6) , Piero Marchetti (7) , Magalie A Ravier (3) , Stéphane Dalle (3) , Philippe Gual (5, 4) , Dany Muller (3) , Guy A. Rutter (6) , Stéphane Servais (2) , Juan L Iovanna (1) , Alice Carrier (1)

1 CRCM - Centre de Recherche en Cancérologie de Marseille
2 N2C - Nutrition, croissance et cancer (U 1069)
3 IGF - Institut de Génomique Fonctionnelle
4 Pôle Digestif
5 C3M - Centre méditerranéen de médecine moléculaire
6 Cell Biology, Department of Medicine
7 Islet Cell Laboratory

The metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). T2D is characterized by insulin resistance resulting from both environmental and genetic factors. A genome-wide association study (GWAS) published in 2010 identified TP53INP1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP53INP1 are prone to redox-driven obesity and insulin resistance. Furthermore, we demonstrate that the reactive oxygen species increase in TP53INP1-deficient cells results from accumulation of defective mitochondria associated with impaired PINK/PARKIN mitophagy. This chronic oxidative stress also favors accumulation of lipid droplets. Taken together, our data provide evidence that the GWAS-identified TP53INP1 gene prevents metabolic syndrome, through a mechanism involving prevention of oxidative stress by mitochondrial homeostasis regulation. In conclusion, this study highlights TP53INP1 as a molecular regulator of redox-driven metabolic syndrome and provides a new preclinical mouse model for metabolic syndrome clinical research.

Keywords: diabetes; mitochondria; ADIPOSE-TISSUE; CELL-DEATH; OXIDATIVE STRESS; TUMOR-SUPPRESSOR; POTENTIAL LINK; OBESITY; CANCER; AUTOPHAGY; INFLAMMATION; EXPRESSION

Domains: Life Sciences [q-bio]; Cancer

Marion Seillier, Laurent Pouyet, Prudence N’guessan, Marie Nollet, Florence Capo, et al.. Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1. EMBO Molecular Medicine, 2015, pp.802-818. ⟨10.15252/emmm.201404318⟩. ⟨hal-01208177⟩