Scientific Report, Olof Idevall-Hagren

Many diseases are associated with disturbed organelle communication. We are trying to understand how such cross talk between cellular compartments are achieved and why they sometimes malfunction in disease.

Scientific Report, Olof Idevall-Hagren

Just like our organs need to “talk” to each other to make our body function properly, the organelles inside each of our cells also need to communicate in order to maintain cell functionality. It is therefore not surprising that many diseases are associated with disturbed organelle communication. We are trying to understand how such cross talk between cellular compartments are achieved and why they sometimes malfunction in disease.

The direct physical contacts between cellular organelles were observed more than 60 years ago, but little is known about their composition. Organelles, such as the ER and mitochondria, are dynamic in cells and their numbers and sizes vary over time, making them difficult to study. We have set up two new techniques that will allow us to directly study these structures. First, we are using a technique called proximity biotinylation in which we introduce a protein known to localize at the contact sites that has been coupled to a biotin ligase. When the cells are cultured in the presence of biotin, this will result in biotinylation of proteins that are in the close proximity of the introduced protein. Subsequent extraction of biotinylated proteins gives us a “map” of all the proteins that reside close to the contacts and will hopefully help us to identify new components within these structures. We have successfully set up the technique and will now identify the proteins through mass spectrometry. The second technique we have developed allow us generate artificial contacts between different cellular organelles using illumination. This optogenetic technique is now well established in the lab, and the acute generation of organelle contacts will allow us to directly investigate their function in the cells.

A proposed role of organelle contacts is to facilitate lipid transfer between the outer membranes of the organelles. One such lipid family is phosphoinositides, whose presence in the outer cell membrane controls a plethora of cellular functions. One of these phosphoinositides, PIP2, undergo concentration changes in insulin secreting cells as they release the hormone, but its role in this process is not known. We used optogenetics to acutely remove or synthesize this lipid in the plasma membrane and found that even small changes in lipid concentration impair Ca2+-influx and suppress insulin secretion, similar to what occurs in diabetes. This manuscript has been submitted and we are following up these findings by investigating to what extent the levels of this lipid is altered in metabolic disease and diabetes.

2015 was an exciting year that saw the birth of our lab. During 2015 we welcomed three new group members: Antje Thonig from Germany joined us in March as a research technician, in September, Beichen Xie from China joined us a Ph.D. student, and late last year My Nguyen from Vietnam also joined as a Ph.D. student. Two postdocs have also been recruited and they are expected to join the lab in the middle of 2016.