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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Insulin Resistance
  • Metabolic Syndrome / physiopathology*
  • Mice
  • Mitophagy*
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / metabolism*
  • Obesity
  • Oxidation-Reduction
  • Oxidative Stress
  • Reactive Oxygen Species / analysis

Substances

  • Nuclear Proteins
  • Reactive Oxygen Species
  • tumor protein 53-induced nuclear protein 1, mouse