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EMBO Mol Med. 2015 Jun;7(6):802-18. doi: 10.15252/emmm.201404318.

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

Author information

1
Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France.
2
Inserm, U1069 Nutrition, Croissance et Cancer (N2C), Tours, France.
3
CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France.
4
Inserm, U1065, C3M Team 8 "Hepatic Complications in Obesity", Nice, France Université de Nice-Sophia-Antipolis, Nice, France Centre Hospitalier Universitaire de Nice, Pôle Digestif Hôpital L'Archet, Nice, France.
5
Cell Biology, Department of Medicine, Imperial College, London, UK.
6
Islet Cell Laboratory, University of Pisa - Cisanello Hospital, Pisa, Italy.
7
Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France alice.carrier@inserm.fr.

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.

KEYWORDS:

autophagy; diabetes; mitochondria; obesity; oxidative stress

PMID:
25828351
PMCID:
PMC4459819
DOI:
10.15252/emmm.201404318
[Indexed for MEDLINE]
Free PMC Article

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