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Leif Groop

Leif Groop

Principal investigator

Leif Groop

The diabetes susceptibility gene clec16a regulates mitophagy.

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

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.

Department/s

  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2014

Language

English

Pages

1577-1590

Publication/Series

Cell

Volume

157

Issue

7

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