SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake

Birgit Honrath, Lina Matschke, Tammo Meyer, Lena Magerhans, Fabiana Perocchi, Goutham K Ganjam, Hans Zischka, Cornelius Krasel, Albert Gerding, Barbara M Bakker, Moritz Bünemann, Stefan Strack, Niels Decher, Carsten Culmsee, Amalia M Dolga

Research output: Contribution to journalArticleAcademicpeer-review

31 Citations (Scopus)

Abstract

Mitochondrial calcium ([Ca(2+)]m) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca(2+)]m uptake upon SK channel activation as detected by time lapse mitochondrial Ca(2+) measurements with the Ca(2+)-binding mitochondria-targeted aequorin and FRET-based [Ca(2+)]m probes. High-resolution respirometry revealed a reduction in mitochondrial respiration and complex I activity upon pharmacological activation and overexpression of mitochondrial SK2 channels resulting in reduced mitochondrial ROS formation. Overexpression of mitochondria-targeted SK2 channels enhanced mitochondrial resilience against neuronal death, and this effect was inhibited by overexpression of a mitochondria-targeted dominant-negative SK2 channel. These findings suggest that SK channels provide neuroprotection by reducing [Ca(2+)]m uptake and mitochondrial respiration in conditions, where sustained mitochondrial damage determines progressive neuronal death.Cell Death and Differentiation advance online publication, 10 March 2017; doi:10.1038/cdd.2017.2.

Original languageEnglish
Pages (from-to)761-773
Number of pages13
JournalCell death and differentiation
Volume24
Issue number5
DOIs
Publication statusPublished - May-2017

Keywords

  • NEURONAL CELL-DEATH
  • POTASSIUM CHANNEL
  • OXIDATIVE STRESS
  • ENDOPLASMIC-RETICULUM
  • HIPPOCAMPAL-NEURONS
  • GLUTAMATE TOXICITY
  • CALCIUM UNIPORTER
  • NA+/CA2+ EXCHANGE
  • K+ CHANNELS
  • MEMBRANE

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