Open AccessDefects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP 53 INP 1
Author(s) -
Seillier Marion,
Pouyet Laurent,
N'Guessan Prudence,
Nollet Marie,
Capo Florence,
Guillaumond Fabienne,
Peyta Laure,
Dumas JeanFrançois,
Varrault Annie,
Bertrand Gyslaine,
Bonnafous Stéphanie,
Tran Albert,
Meur Gargi,
Marchetti Piero,
Ravier Magalie A,
Dalle Stéphane,
Gual Philippe,
Muller Dany,
Rutter Guy A,
Servais Stéphane,
Iovanna Juan L,
Carrier Alice
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404318
Subject(s) - mitophagy , metabolic syndrome , oxidative stress , insulin resistance , parkin , mitochondrion , oxidative phosphorylation , biology , microbiology and biotechnology , medicine , endocrinology , biochemistry , obesity , autophagy , disease , apoptosis , parkinson's disease
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 TP 53 INP 1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP 53 INP 1 are prone to redox‐driven obesity and insulin resistance. Furthermore, we demonstrate that the reactive oxygen species increase in TP 53 INP 1‐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 TP 53 INP 1 gene prevents metabolic syndrome, through a mechanism involving prevention of oxidative stress by mitochondrial homeostasis regulation. In conclusion, this study highlights TP 53 INP 1 as a molecular regulator of redox‐driven metabolic syndrome and provides a new preclinical mouse model for metabolic syndrome clinical research.