Mitochondrial Defects Seen to Contribute to Wolfram Syndrome

While research into the genetic condition Wolfram syndrome has long focused on a cellular component called the endoplasmic reticulum, researchers in Estonia widened their view, and discovered that mitochondria are key contributors to the disease.

In addition to advancing an understanding of this syndrome, the study, “Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome,” published recently in the journal PLOS Biology, identified structures that could be targeted in new treatment strategies for the condition.

The genetic mutation causing Wolfram syndrome, marked by high blood sugar levels in children resulting from a shortage of the hormone insulin, disrupts a protein called wolframin — a component of the endoplasmic reticulum, which, among other duties, is responsible for the production of proteins and is a storage point for calcium ions in the cell.

Professor Allen Kaasik at the University of Tartu noted that the main symptoms of Wolfram syndrome — deafness, the death of optic nerves, and psychiatric disorders — were suspiciously similar to those observed in patients with mitochondrial conditions.

“The majority of previous research has focused on the endoplasmic reticulum and ignores the fact that most of the manifestations of Wolfram syndrome resemble those of mitochondrial diseases,” said Dr. Kaasik in a news release.

Studying neurons with the help of a host of molecular laboratory and imaging methods, the researchers came up with evidence of a chain of events, starting with mutated wolframin and leading up to mitochondria.

Their work demonstrated that the defective wolframin protein made the endoplasmic reticulum dysfunctional, lowering the amounts of calcium it released within a cell. The lower calcium levels, in turn, prevented mitochondria from dividing as usual and slowed their energy production, leading to the observed delay in neuronal development.

The findings are likely to impact the way researchers look at Wolfram syndrome, and also produced some unexpected links. The changes caused by mutant wolframin were tied to the PINK1-Parkin pathway, a molecular mitochondrial quality control system that scientists think may contribute to Parkinson’s disease. Also, the researchers discovered that a mild disruption of endoplasmic reticulum function caused a severe disturbance in calcium release and mitochondrial activity.

Reports of wolframin not functioning properly have come from scientists studying psychiatric ills not related to Wolfram syndrome, so the findings might also open a new understanding of how mitochondria contributed to psychiatric disorders.