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

Autor:	Seillier M; Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France., Pouyet L; Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France., N'Guessan P; Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France., Nollet M; Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France., Capo F; Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France., Guillaumond F; Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France., Peyta L; Inserm, U1069 Nutrition, Croissance et Cancer (N2C), Tours, France., Dumas JF; Inserm, U1069 Nutrition, Croissance et Cancer (N2C), Tours, France., Varrault A; CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France., Bertrand G; CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France., Bonnafous S; 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., Tran A; 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., Meur G; Cell Biology, Department of Medicine, Imperial College, London, UK., Marchetti P; Islet Cell Laboratory, University of Pisa - Cisanello Hospital, Pisa, Italy., Ravier MA; CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France., Dalle S; CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France., Gual P; 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., Muller D; CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France., Rutter GA; Cell Biology, Department of Medicine, Imperial College, London, UK., Servais S; Inserm, U1069 Nutrition, Croissance et Cancer (N2C), Tours, France., Iovanna JL; Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France., Carrier A; Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France alice.carrier@inserm.fr.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2015 Jun; Vol. 7 (6), pp. 802-18.
DOI:	10.15252/emmm.201404318
Abstrakt:	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. (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze:	MEDLINE
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