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 susc...
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201404318 |
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| author | Marion Seillier Laurent Pouyet Prudence N'Guessan Marie Nollet Florence Capo Fabienne Guillaumond Laure Peyta Jean‐François Dumas Annie Varrault Gyslaine Bertrand Stéphanie Bonnafous Albert Tran Gargi Meur Piero Marchetti Magalie A Ravier Stéphane Dalle Philippe Gual Dany Muller Guy A Rutter Stéphane Servais Juan L Iovanna Alice Carrier |
| author_facet | Marion Seillier Laurent Pouyet Prudence N'Guessan Marie Nollet Florence Capo Fabienne Guillaumond Laure Peyta Jean‐François Dumas Annie Varrault Gyslaine Bertrand Stéphanie Bonnafous Albert Tran Gargi Meur Piero Marchetti Magalie A Ravier Stéphane Dalle Philippe Gual Dany Muller Guy A Rutter Stéphane Servais Juan L Iovanna Alice Carrier |
| author_sort | Marion Seillier |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a391b04c6a3242c3a64fb5dbffab3422 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a391b04c6a3242c3a64fb5dbffab34222025-08-20T03:43:26ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-03-017680281810.15252/emmm.201404318Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1Marion Seillier0Laurent Pouyet1Prudence N'Guessan2Marie Nollet3Florence Capo4Fabienne Guillaumond5Laure Peyta6Jean‐François Dumas7Annie Varrault8Gyslaine Bertrand9Stéphanie Bonnafous10Albert Tran11Gargi Meur12Piero Marchetti13Magalie A Ravier14Stéphane Dalle15Philippe Gual16Dany Muller17Guy A Rutter18Stéphane Servais19Juan L Iovanna20Alice Carrier21Inserm, U1068, CRCMInserm, U1068, CRCMInserm, U1068, CRCMInserm, U1068, CRCMInserm, U1068, CRCMInserm, U1068, CRCMInserm, U1069, Nutrition, Croissance et Cancer (N2C)Inserm, U1069, Nutrition, Croissance et Cancer (N2C)CNRS, UMR5203, Inserm, U661, Universités de Montpellier 1 & 2, IGFCNRS, UMR5203, Inserm, U661, Universités de Montpellier 1 & 2, IGFInserm, U1065, C3M, Team 8 “Hepatic Complications in Obesity”Inserm, U1065, C3M, Team 8 “Hepatic Complications in Obesity”Cell Biology, Department of Medicine, Imperial CollegeIslet Cell Laboratory, University of Pisa – Cisanello HospitalCNRS, UMR5203, Inserm, U661, Universités de Montpellier 1 & 2, IGFCNRS, UMR5203, Inserm, U661, Universités de Montpellier 1 & 2, IGFInserm, U1065, C3M, Team 8 “Hepatic Complications in Obesity”CNRS, UMR5203, Inserm, U661, Universités de Montpellier 1 & 2, IGFCell Biology, Department of Medicine, Imperial CollegeInserm, U1069, Nutrition, Croissance et Cancer (N2C)Inserm, U1068, CRCMInserm, U1068, CRCMAbstract 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.https://doi.org/10.15252/emmm.201404318autophagydiabetesmitochondriaobesityoxidative stress |
| spellingShingle | Marion Seillier Laurent Pouyet Prudence N'Guessan Marie Nollet Florence Capo Fabienne Guillaumond Laure Peyta Jean‐François Dumas Annie Varrault Gyslaine Bertrand Stéphanie Bonnafous Albert Tran Gargi Meur Piero Marchetti Magalie A Ravier Stéphane Dalle Philippe Gual Dany Muller Guy A Rutter Stéphane Servais Juan L Iovanna Alice Carrier Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1 EMBO Molecular Medicine autophagy diabetes mitochondria obesity oxidative stress |
| title | Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1 |
| title_full | Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1 |
| title_fullStr | Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1 |
| title_full_unstemmed | Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1 |
| title_short | Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP53INP1 |
| title_sort | defects in mitophagy promote redox driven metabolic syndrome in the absence of tp53inp1 |
| topic | autophagy diabetes mitochondria obesity oxidative stress |
| url | https://doi.org/10.15252/emmm.201404318 |
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