Jun 2015 EMBO molecular medicine

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

Auteurs

Seillier M, Pouyet L, N'Guessan P, Nollet M, Capo F, Guillaumond F, Peyta L, Dumas JF, Varrault A, Bertrand G, Bonnafous S, Tran A, Meur G, Marchetti P, Ravier MA, Dalle S, Gual P, Muller D, Rutter GA, Servais S, Iovanna JL, Carrier A

Résumé

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.

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