Defects in mitophagy promote redox‐driven metabolic syndrome in the absence of TP 53 INP 1

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.

The stress protein TP53INP1 plays a tumor suppressive role by regulating metabolic homeostasis

“…This redox role is also important for the control of lipid metabolism, both in vitro (TP53INP1-deficient cells accumulate lipid droplets) and in vivo (fat mass is aberrantly abundant in TP53INP1-deficient mice). Altogether, these observations reveal a mechanism for the genome-wide association study (GWAS)-identified role of TP53INP1 in Type 2 Diabetes promoted by obesity [67]: TP53INP1 participation in mitophagy prevents the accumulation of mitochondria producing ROS which favor lipid accumulation [21].…”

“…Nuclear localization is also observed upon oxidative stress through redox-driven sumoylation [20]. In other contexts, TP53INP1 is found in the cytoplasm, in autophagosomes during autophagy, as well as in mitochondria [17,21]. The mechanism responsible for addressing TP53INP1 to these different cellular compartments remains to be elucidated.…”

“…In vivo, the TP53INP1-encoding gene was shown to be upregulated during inflammation in the pancreas [11,34], during oxidative stress (induced by diquat) in the liver [35], in the thymus upon whole-body irradiation or dexamethasone injection [31], in mouse spermatogonial stem cells of irradiated testis [36], and in the liver of High-Fat Diet-induced obese mice [21].…”

“…Long-term overexpression of TP53INP1 favors the running of autophagy which is rather pro-apoptotic [17]. Interestingly, TP53INP1 also binds PINK1 and Parkin, which are involved in mitophagy, an important mitochondrial quality control mechanism that eliminates damaged mitochondria by autophagy [21]. Mitophagy is impaired in TP53INP1-deficient mice, which contribute to the accumulation of defective mitochondria in TP53INP1-deficient cells [21].…”

“…Interestingly, TP53INP1 also binds PINK1 and Parkin, which are involved in mitophagy, an important mitochondrial quality control mechanism that eliminates damaged mitochondria by autophagy [21]. Mitophagy is impaired in TP53INP1-deficient mice, which contribute to the accumulation of defective mitochondria in TP53INP1-deficient cells [21]. Production of ROS is increased when mitochondria are defective, thus the involvement of TP53INP1 in mitophagy is crucial for the control of ROS levels.…”