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

EMBO Molecular Medicine

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 】

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.

Synopsis

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.

• TP53INP1 is known for its tumor suppressive activity due to its implication in redox control.
• TP53INP1 also plays a role in T2D prevention by regulating redox-associated lipid metabolism.
• Excess of ROS in TP53INP1-deficient mice stems from accumulation of defective mitochondria producing ROS.
• Accumulation of mitochondria in TP53INP1-deficient mice is due in part from defective autophagy, and in particular mitophagy.

【 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.