Inhibition of p53 preserves Parkin-mediated mitophagy and pancreatic β-cell function in diabetes
Abstract
Tumor suppressor p53 has been known to have a broader role that extends to the regulation of energy metabolism. We investigated the role of islet p53 and found that genetic and pharmacological inhibition of p53 preserves insulin secretion and glucose tolerance in both streptozotocin-induced type 1 and db/db mouse models of type 2 diabetes. Glucolipotoxicy induces accumulation of p53 in the cytosol via oxidative stress and endoplasmic reticulum stress. Cytosolic p53 inhibits the autophagic clearance of damaged mitochondria by an inhibitory protein-protein interaction with Parkin, leading to the impairment of mitochondrial energetics and subsequent insulin secretion signals in islet β-cells.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- February 2014
- DOI:
- 10.1073/pnas.1318951111
- Bibcode:
- 2014PNAS..111.3116H