The role of calcium-activated potassium channels in neuronal mitochondria

• Applicant: Dr. Amalia Dolga
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Pharmacology ; Cell Biology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249667320

• Final Report Year: 2017

Final Report Abstract

Despite the markedly reduced resources, the work of this project has addressed the key questions about the function of SK2 channels in the cell death pathways, in particular in models of mitochondrial oxidative stress and ER stress. The distribution of SK channels in neuronal cells has been established by cellular fractionation and mitochondrial/ER purification. To achieve this, successful collaborations with different research groups (Prof. H. Zischka, Prof. F. Perocchi, Ludwig-Maximilians-Universität Munchen) have been established. This project allowed the implementation of a pure semi-automated method of mitochondrial isolation from either brain tissue or cell cultures. This method provided reproducible and very good quality of mitochondria, as measured by high-resolution respirometry or Seahorse measurements. In addition, several methods of mitochondrial calcium uptake were established and implemented in the lab. The successful implementation of mitochondrial calcium uptake were performed in close collaboration with Prof. M. Bünemann (University of Marburg) and Prof. F. Perocchi (Ludwig-Maximilians-Universität Munchen). The specificity of SK channel modulators and their effects on neuronal activity was achieved in collaboration with Prof. N. Decher (University of Marburg). This project shed light on the neuroprotective potential of SK channel activation and how these channels are affecting mitochondrial respiration, mitochondrial calcium uptake, and mitochondrial superoxide formation. We have demonstrated that by either opening of SK channels or by enrichment of SK2 channels in mitochondria, neuronal survival is preserved in conditions of oxidative stress.

Publications

• (2017) Glucose-regulated protein 75 determines ER-mitochondrial coupling and sensitivity to oxidative stress in neuronal cells. Cell death discovery 3 17076
  Honrath B, Metz I, Bendridi N, Rieusset N, Culmsee C, Dolga A
  
• (2017) Small conductance Ca2+-activated K+ channels in the plasma membrane, mitochondria and the ER: Pharmacology and implications in neuronal diseases. Neurochemistry international 109 13–23
  Honrath B, KrabbendamI, Culmsee C, Dolga AM
  
• (2018) Mitochondrial Ca2+-activated K+ channels and their role in cell life and death pathways. Cell calcium 69 101–111
  Krabbendam I, Honrath B, Culmsee C, Dolga AM
  
• SK channel activation modulates mitochondrial respiration and attenuates neuronal HT-22 cell damage induced by H2O2. Neurochem Int. 2015 Feb;81:63-75
  Richter M, Nickel C, Apel L, Kaas A, Dodel R, Culmsee C, Dolga AM
  
• Activation of SK2 channels preserves ER Ca²⁺ homeostasis and protects against ER stress-induced cell death. Cell Death Differ. 2016 May;23(5):814-27
  Richter M, Vidovic N, Honrath B, Mahavadi P, Dodel R, Dolga AM, Culmsee C
  
• Lithium protects hippocampal progenitors, cognitive performance and hypothalamus-pituitary function after irradiation to the juvenile rat brain. Oncotarget. 2017 Mar 16
  Zhou K, Xie C, Wickström M, Dolga AM, Zhang Y, Li T, Xu Y, Culmsee C, Kogner P, Zhu C, Blomgren K
  
• SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake. Cell Death Differ. 2017 Mar 10
  Honrath B, Matschke L, Meyer T, Magerhans L, Perocchi F, Ganjam GK, Zischka H, Krasel C, Gerding A, Bakker BM, Bünemann M, Strack S, Decher N, Culmsee C, Dolga AM