Inhibition of p53 preserves Parkin-mediated mitophagy and pancreatic β-cell function in diabetes.

Abstract

Mitochondrial compromise is a fundamental contributor to pancreatic β-cell failure in diabetes. Previous studies have demonstrated a broader role for tumor suppressor p53 that extends to the modulation of mitochondrial homeostasis. However, the role of islet p53 in glucose homeostasis has not yet been evaluated. Here we show that p53 deficiency protects against the development of diabetes in streptozotocin (STZ)-induced type 1 and db/db mouse models of type 2 diabetes. Glucolipotoxicity stimulates NADPH oxidase via receptor for advanced-glycation end products and Toll-like receptor 4. This oxidative stress induces the accumulation of p53 in the cytosolic compartment of pancreatic β-cells in concert with endoplasmic reticulum stress. Cytosolic p53 disturbs the process of mitophagy through an inhibitory interaction with Parkin and induces mitochondrial dysfunction. The occurrence of mitophagy is maintained in STZ-treated p53(-/-) mice that exhibit preserved glucose oxidation capacity and subsequent insulin secretion signaling, leading to better glucose tolerance. These protective effects are not observed when Parkin is deleted. Furthermore, pifithrin-α, a specific inhibitor of p53, ameliorates mitochondrial dysfunction and glucose intolerance in both STZ-treated and db/db mice. Thus, an intervention with cytosolic p53 for a mitophagy deficiency may be a therapeutic strategy for the prevention and treatment of diabetes.

• Authors: Atsushi Hoshino, Makoto Ariyoshi, Yoshifumi Okawa, Satoshi Kaimoto, Motoki Uchihashi, Kuniyoshi Fukai, Eri Iwai-Kanai, Koji Ikeda, Tomomi Ueyama, Takehiro Ogata, Satoaki Matoba
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 8 Pg. 3116-21 (Feb 25 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24516131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzothiazoles
• Insulin
• Tumor Suppressor Protein p53
• Toluene
• pifithrin
• Ubiquitin-Protein Ligases
• parkin protein

Topics

• Animals
• Benzothiazoles (pharmacology)
• Cell Line
• Diabetes Mellitus (physiopathology)
• Endoplasmic Reticulum Stress (physiology)
• Flow Cytometry
• Fluorescent Antibody Technique
• Immunoblotting
• Immunohistochemistry
• Immunoprecipitation
• Insulin (metabolism)
• Insulin Secretion
• Insulin-Secreting Cells (metabolism, physiology)
• Mice
• Mice, Knockout
• Microscopy, Electron
• Mitophagy (physiology)
• Oxidative Stress (physiology)
• RNA Interference
• Toluene (analogs & derivatives, pharmacology)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, genetics, metabolism)
• Ubiquitin-Protein Ligases (metabolism)