The diabetes susceptibility gene clec16a regulates mitophagy.

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

Research output: Contribution to journalArticlepeer-review

108 Citations (SciVal)

Abstract

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.
Original languageEnglish
Pages (from-to)1577-1590
JournalCell
Volume157
Issue number7
DOIs
Publication statusPublished - 2014

Subject classification (UKÄ)

  • Endocrinology and Diabetes

Fingerprint

Dive into the research topics of 'The diabetes susceptibility gene clec16a regulates mitophagy.'. Together they form a unique fingerprint.

Cite this