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The diabetes susceptibility gene clec16a regulates mitophagy.

Soleimanpour, Scott A; Gupta, Aditi; Bakay, Marina; Ferrari, Alana M; Groff, David N; Fadista, Joao LU ; Spruce, Lynn A; Kushner, Jake A; Groop, Leif LU and Seeholzer, Steven H, et al. (2014) In Cell 157(7). p.1577-1590
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... (More)
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. (Less)
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type
Contribution to journal
publication status
published
subject
in
Cell
volume
157
issue
7
pages
1577 - 1590
publisher
Cell Press
external identifiers
  • pmid:24949970
  • wos:000340941900013
  • scopus:84903196141
ISSN
1097-4172
DOI
10.1016/j.cell.2014.05.016
language
English
LU publication?
yes
id
4ef0dfda-149c-4c11-a153-c81111226361 (old id 4527439)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24949970?dopt=Abstract
date added to LUP
2014-07-06 19:51:35
date last changed
2017-11-12 03:01:43
@article{4ef0dfda-149c-4c11-a153-c81111226361,
  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.},
  author       = {Soleimanpour, Scott A and Gupta, Aditi and Bakay, Marina and Ferrari, Alana M and Groff, David N and Fadista, Joao and Spruce, Lynn A and Kushner, Jake A and Groop, Leif and Seeholzer, Steven H and Kaufman, Brett A and Hakonarson, Hakon and Stoffers, Doris A},
  issn         = {1097-4172},
  language     = {eng},
  number       = {7},
  pages        = {1577--1590},
  publisher    = {Cell Press},
  series       = {Cell},
  title        = {The diabetes susceptibility gene clec16a regulates mitophagy.},
  url          = {http://dx.doi.org/10.1016/j.cell.2014.05.016},
  volume       = {157},
  year         = {2014},
}