Mitochondrial dysfunction in oxidative stress: On the impact of neuronal KCa channels & calcium signaling in neurodegeneration

Honrath, B., 2017, [Groningen]: University of Groningen. 232 p.

Research output: ThesisThesis fully internal (DIV)Academic

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  • Birgit Honrath
Neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease are characterized by an irreversible loss of neurons in different brain areas. So far, treatment options only target symptoms but not the disease pathology.
In this thesis, we exploited new protective strategies for the treatment of neurodegenerative diseases by investigating small conductance calcium-activated potassium (KCa) channels and associated calcium signaling. KCa channels prevent increases in neuronal excitability, a key factor that contributes to neuronal death.
We found that pharmacological activation of KCa channels protected neuronal cells from oxidative cell death associated with mitochondrial dysfunction through regulating mitochondrial respiration and mitochondrial calcium uptake. Mitochondrial function also depends on calcium transfer between the endoplasmic reticulum (ER) and mitochondria. Using two approaches, we showed that this signaling axis has a substantial impact on neuronal survival. On the one hand, blocking this route of calcium prevented oxidative cell death. On the other hand, promoting ER-mitochondrial interactions increased mitochondrial calcium uptake, impaired mitochondrial respiration and accelerated cell death. In conditions of enhanced ER-mitochondrial connectivity, KCa channel activation still provided protection against oxidative stress induced by the neurotransmitter glutamate but not by the anti-cancer agent auranofin, indicating potential effects of KCa channels beyond neuroprotection. Furthermore, we found that KCa channels are involved in the development of epilepsy, a disorder characterized by neuronal hyperactivity, and we identified a potential new regulatory mechanism of KCa channels by small non-coding microRNAs.
Thus, this thesis elaborated KCa channel activation as a strategy to preserve neuronal cell survival in different neuropathological conditions.
Translated title of the contributionMitochondriale dysfunctie in oxidatieve stress – over de impact van neuronale KCa kanalen en calcium signalering in neurodegeneratie
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Schmidt, Martina, Supervisor
  • Dolga, Amalia, Co-supervisor
  • Culmsee, C, Co-supervisor, External person
  • Eisel, Ulrich, Assessment committee
  • Bultynck, Geert, Assessment committee, External person
  • Kushner, Steven A., Assessment committee, External person
Award date8-Dec-2017
Place of Publication[Groningen]
Print ISBNs978-94-034-0176-8
Electronic ISBNs978-94-034-0175-1
Publication statusPublished - 2017

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