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

Abstract : 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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Submitted on : Friday, October 2, 2015 - 9:50:02 AM
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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, Wiley Open Access, 2015, pp.802-818. ⟨10.15252/emmm.201404318⟩. ⟨hal-01208177⟩



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