EMBO Molecular Medicine | |
Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1 | |
Marion Seillier4  Laurent Pouyet4  Prudence N'Guessan4  Marie Nollet4  Florence Capo4  Fabienne Guillaumond4  Laure Peyta2  Jean-François Dumas2  Annie Varrault1  Gyslaine Bertrand1  Stéphanie Bonnafous3  Albert Tran3  Gargi Meur5  Piero Marchetti6  Magalie A Ravier1  Stéphane Dalle1  Philippe Gual3  Dany Muller1  Guy A Rutter5  Stéphane Servais2  Juan L Iovanna4  | |
[1] CNRS, UMR5203, Inserm, U661, Universités de Montpellier 1 & 2, IGF, Montpellier, France;Inserm, U1069, Nutrition, Croissance et Cancer (N2C), Tours, France;Inserm, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France;Inserm, U1068, CRCM, Marseille, France;Cell Biology, Department of Medicine, Imperial College, London, UK;Islet Cell Laboratory, University of Pisa – Cisanello Hospital, Pisa, Italy | |
关键词: autophagy; diabetes; mitochondria; obesity; oxidative stress; | |
DOI : 10.15252/emmm.201404318 | |
来源: Wiley | |
【 摘 要 】
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. TP53INP1, a p53-regulated protein with antioxidant and tumor suppressive functions, is shown to prevent redox-driven obesity, which leads to insulin resistance and type 2 diabetes (T2D), likely by impacting on mitochondria homeostasis and mitophagy.Abstract
Synopsis
【 授权许可】
CC BY
© 2015 The Authors. Published under the terms of the CC BY 4.0 license
Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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