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Diabetes Linked to Faulty Mitochondria Disposal Pathway

By BiotechDaily International staff writers
Posted on 08 Jul 2014
Image: Mouse fibroblast shows Clec16a (red), the lysosome protein Lamp1 (green), the autophagosome protein LC3 (blue), and DNA (gray). The yellow overlap of the red and green stains shows that Clec16a resides in the endolysosomal compartment, part of the cellular disposal system used in mitophagy (Photo courtesy of the University of Pennsylvania).
Image: Mouse fibroblast shows Clec16a (red), the lysosome protein Lamp1 (green), the autophagosome protein LC3 (blue), and DNA (gray). The yellow overlap of the red and green stains shows that Clec16a resides in the endolysosomal compartment, part of the cellular disposal system used in mitophagy (Photo courtesy of the University of Pennsylvania).
A molecular pathway that regulates the disposal of defective mitochondria (mitophagy) has been cited as a potential target for prevention and control of diabetes and certain other diseases.

Clec16a (C-type lectin domain family 16, member A) has been identified as a disease susceptibility gene for type I diabetes, multiple sclerosis, and adrenal dysfunction, but its function is unknown. In the current study investigators at the University of Pennsylvania (Philadelphia, USA) worked with a genetically engineered mouse model that lacked Clec16a in their pancreas.

The investigators reported in the June 19, 2014, online edition of the journal Cell that normally Clec16a interacted with the E3 ubiquitin ligase Nrdp1. Loss of Clec16a led to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a had abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal pancreatic beta-cell function.

Additionally, the investigators reported that patients harboring a pro-diabetic SNP (single nucleotide polymorphism) mutation in the Clec16a gene had reduced islet Clec16a expression and reduced insulin secretion. Thus, Clec16a controlled beta-cell function and prevented diabetes by regulating mitophagy.

"The ultimate result of the deletion of Clec16a is an accumulation of unhealthy mitochondria, leading to less insulin being secreted by the beta-cells," said senior author Dr. Doris Stoffers, professor of medicine at the University of Pennsylvania. "This pathway could be targeted for prevention and control of diabetes and may extend to the pathogenesis of other Clec16a- and Parkin-associated diseases."

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