Publication

SK channels at the ER-mitochondrial interface preserve neuronal survival in conditions of enhanced calcium transfer and impaired mitochondrial bioenergetics

Honrath, B., Krabbendam, I., IJsebaart, C., Pegoretti, V., Schmidt, M., Culmsee, C. & Dolga, A. M., 2017.

Research output: Contribution to conferencePosterAcademic

The crosstalk between the endoplasmic reticulum (ER) and mitochondria facilitates calcium transfer between these organelles, thereby maintaining the driving force for calcium into the mitochondrial matrix to facilitate mitochondrial respiration and ATP production. However, a pathological increase in ER-mitochondrial coupling (EMC) induces mitochondrial calcium overload and mitochondrial damage which has been linked to the progression of neurodegenerative diseases. calcium-activated potassium (SK) channels attenuate neuronal cell death by preventing mitochondrial superoxide formation and mitochondrial calcium dysregulation, and are therefore a promising target for the treatment of neurodegenerative diseases.
In this study, we expressed genetically-encoded ER-mitochondrial linkers which heterodimerize to link ER and mitochondria upon addition of rapamycin in neuronal HT22 cells. We found that cell death induced by glutamate was potentiated in conditions of enhanced EMC, and both, SK channel activation, and enrichment of a mitochondria-targeted SK2 channel variant protected against glutamate toxicity. Using mitochondrial GFP-aequorin for calcium measurements, we show that EML formation indeed enhanced mitochondrial calcium uptake in response to calcium chloride stimulation. Further, we found that strengthening ER-mitochondrial connectivity impaired basal mitochondrial respiration and attenuated maximal uncoupled respiration as assessed by extracellular flux analysis. Together, our results indicate that mitochondrial SK channel activation was able to prevent toxicity induced by increased EMC which leads to dysfunctional calcium homeostasis and impaired respiration. These results highlight the importance of mitochondrial SK channel isoforms in protection against neuronal cell death through enhancing mitochondrial resilience.
Original languageEnglish
Publication statusPublished - 2017
EventNeurochemical Conference 2017: Advances in molecular and epigenetic mechanisms in neurodegeneration and neuroinflammation: novel therapeutic approaches - Warsaw, Poland
Duration: 18-Oct-201720-Oct-2017

Conference

ConferenceNeurochemical Conference 2017
CountryPoland
CityWarsaw
Period18/10/201720/10/2017

Event

Neurochemical Conference 2017: Advances in molecular and epigenetic mechanisms in neurodegeneration and neuroinflammation: novel therapeutic approaches

18/10/201720/10/2017

Warsaw, Poland

Event: Conference

ID: 49843743