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Cell. 2014 Jun 19;157(7):1577-90. doi: 10.1016/j.cell.2014.05.016.

The diabetes susceptibility gene Clec16a regulates mitophagy.

Author information

1
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and the Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
2
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and the Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
3
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
4
Lund University Diabetes Center, Department of Clinical Sciences, Diabetes & Endocrinology, Skåne University Hospital, Lund University, SE-205 02 Malmö, Sweden.
5
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
6
McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
9
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and the Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: stoffers@mail.med.upenn.edu.

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.

PMID:
24949970
PMCID:
PMC4184276
DOI:
10.1016/j.cell.2014.05.016
[Indexed for MEDLINE]
Free PMC Article

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