The exact role of the Clec16a (C-type lectin domain family 16) gene in encouraging susceptibility to type 1 diabetes may have been discovered recently when scientists discovered that the gene regulates the destruction of mitochondria, which are the energy factories of cells. The pathway this gene uses can be targeted to develop potential cures against type 1 diabetes, and even autoimmune conditions like multiple sclerosis.
The gene specifically plays a role in a pancreatic pathway used to produced insulin. Some people with a variation in the gene sequence near Clec16a show a reduction in insulin secretion. A team of researchers, headed by Scott A. Soleimanpour showed, in a new study, the way the gene controls beta cell function in the islet cells, and hence insulin production. Their research appears in this week’s edition of the journal Cell, according to a press release.
Beta cells in the pancreas tend to be concentrated with mitochondria, due to the high levels of energy consumption needed to secrete insulin. Mitochondria provide a continuous supply of ATP, a major energy component. When mitochondria aren't functioning properly, they undergo a self-eating process known as mitophagy, which makes room for good, fully-functioning mitochondria. However, Clec16a controls beta-cell function in this disposal pathway, and people with variations in the gene may end up with a form of Clec16a that hinders mitophagy.
But changes in the intracellular environment result in mitochondria disrupting ATP synthesis and cell death. But before defective mitochondria can cause cell death they are selectively eliminated by a cellular pathwayl, in a process called mitophagy. Clec16a controls beta-cell function in this disposal pathway and is thought to prevent diabetes-related mitophagy.
The team found that Clec16a interacts with an enzyme called Nrdp1, which works through another protein called Parkin. Normally, Parkin regulates mitophagy by initially tagging unhealthy mitochondria for disposal. They tested the effect of depleted levels of Clec16a on mice, and found that it led to an increase in Parkin, a master regulator of mitophagy. Ultimately, it led to lower production of ATP, and thus, lower levels of insulin. "The ultimate result of the deletion of Clec16a is an accumulation of unhealthy mitochondria, leading to less insulin being secreted by the beta cells," co-author Doris Stoffers said in the press release.
The researchers then used islet cells to determine if a small variation in the DNA sequence near the Clec16a gene directly affected the gene's normal expression and function. Individuals with this gene modification were less likely to have Clec16a expressed in islet cells, while also showing slightly higher levels of blood sugar. From this, the team concluded that, in a normal state, Clec16a controls beta cell function, and may prevent diabetes by controlling mitophagy.
"In 2007, our genomics team found the first gene in a genome-wide search to play a major role in type 1 diabetes, but we did not know its function," said co-senior author Dr. Hakon Hakonarson, director of the Center for Applied Genomics at The Children's Hospital of Philadelphia, in the release. "Now we understand how this gene plays a critical role in regulating insulin metabolism." The researchers are hoping that targeting this pathway will help in advancing therapy for diabetes, and other Clec16a and Parkin-associated diseases.
Source: Soleimanpour S, Stoffers D, Bakay M, et al. The Diabetes Susceptibility Gene Clec16a Regulates Mitophagy. Cell. 2014.