title: 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.
authors.affiliation: Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Seillier
authors.affiliation: Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Pouyet
authors.affiliation: Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France.
authors.forename: Prudence
authors.initials: P
authors.lastname: N'Guessan
authors.affiliation: Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Nollet
authors.affiliation: Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Capo
authors.affiliation: Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Guillaumond
authors.affiliation: Inserm, U1069 Nutrition, Croissance et Cancer (N2C), Tours, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Peyta
authors.affiliation: Inserm, U1069 Nutrition, Croissance et Cancer (N2C), Tours, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dumas
authors.affiliation: CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Varrault
authors.affiliation: CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France.
authors.forename: Gyslaine
authors.initials: G
authors.lastname: Bertrand
authors.affiliation: 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.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bonnafous
authors.affiliation: 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.
authors.forename: Albert
authors.initials: A
authors.lastname: Tran
authors.affiliation: Cell Biology, Department of Medicine, Imperial College, London, UK.
authors.forename: Gargi
authors.initials: G
authors.lastname: Meur
authors.affiliation: Islet Cell Laboratory, University of Pisa - Cisanello Hospital, Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France.
authors.forename: Magalie A
authors.initials: MA
authors.lastname: Ravier
authors.affiliation: CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dalle
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gual
authors.affiliation: CNRS, UMR5203, Inserm, U661 Universités de Montpellier 1 & 2, IGF, Montpellier, France.
authors.forename: Dany
authors.initials: D
authors.lastname: Muller
authors.affiliation: Cell Biology, Department of Medicine, Imperial College, London, UK.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Inserm, U1069 Nutrition, Croissance et Cancer (N2C), Tours, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Servais
authors.affiliation: Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
authors.affiliation: Inserm, U1068, CRCM, Marseille, France Institut Paoli-Calmettes, Marseille, France Aix-Marseille Université, Marseille, France CNRS, UMR7258, CRCM, Marseille, France alice.carrier@inserm.fr.
authors.forename: Alice
authors.initials: A
authors.lastname: Carrier
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000503:physiopathology*; D051379:Mice; D063306:Mitophagy; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D009765:Obesity; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000032:analysis
chemical_list: D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; C518507:tumor protein 53-induced nuclear protein 1, mouse
keywords: autophagy; diabetes; mitochondria; obesity; oxidative stress
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