The diabetes susceptibility gene clec16a regulates mitophagy.

Summary, in English

Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis, and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal β cell function. Indeed, pancreatic Clec16a is required for normal glucose-stimulated insulin release. Moreover, patients harboring a diabetogenic SNP in the Clec16a gene have reduced islet Clec16a expression and reduced insulin secretion. Thus, Clec16a controls β cell function and prevents diabetes by controlling mitophagy. This pathway could be targeted for prevention and control of diabetes and may extend to the pathogenesis of other Clec16a- and Parkin-associated diseases.

• Author: Scott A Soleimanpour; Aditi Gupta; Marina Bakay; Alana M Ferrari; David N Groff; Joao Fadista; Lynn A Spruce; Jake A Kushner; Leif Groop; Steven H Seeholzer; Brett A Kaufman; Hakon Hakonarson; Doris A Stoffers
• Department/s: Translational Muscle Research; EXODIAB: Excellence of Diabetes Research in Sweden
• Publishing year: 2014
• Language: English
• Pages: 1577-1590
• Publication/Series: Cell
• Volume: 157
• Issue: 7
• Links: http://www.ncbi.nlm.nih.gov/pubmed/24949970?dopt=Abstract; http://dx.doi.org/10.1016/j.cell.2014.05.016
• Document type: Journal article
• Publisher: Cell Press
• Topic: Endocrinology and Diabetes
• Status: Published
• Research group: Genomics, Diabetes and Endocrinology
• ISBN/ISSN/Other: ISSN: 1097-4172