Impaired Bioenergetics in Mutant Mitochondrial DNA Determines Cell Fate During Seizure-Like Activity
| Autor: | Stjepana Kovac, Matthew C. Walker, Andrey Y. Abramov, Elisavet Preza, Henry Houlden |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death Mitochondrial DNA Cell Respiration Cell Neuroscience (miscellaneous) Cell fate determination DNA Mitochondrial Cell Line 03 medical and health sciences Cellular and Molecular Neuroscience Adenosine Triphosphate 0302 clinical medicine Seizures medicine Humans Cell Lineage Calcium Signaling Fibroblast Membrane Potential Mitochondrial Membrane potential Chemistry Fibroblasts NAD Mitochondria Cell biology 030104 developmental biology medicine.anatomical_structure Neurology Cell culture Mutation Calcium Energy Metabolism Oxidation-Reduction 030217 neurology & neurosurgery Intracellular |
| Zdroj: | Molecular Neurobiology. 56:321-334 |
| ISSN: | 1559-1182 0893-7648 |
| DOI: | 10.1007/s12035-018-1078-9 |
| Popis: | Mutations in genes affecting mitochondrial proteins are increasingly recognised in patients with epilepsy, but the factors determining cell fate during seizure activity in these mutations remain unknown. Fluorescent dye imaging techniques were applied to fibroblast cell lines from patients suffering from common mitochondrial mutations and to age-matched controls. Using live cell imaging techniques in fibroblasts, we show that fibroblasts with mutations in the mitochondrial genome had reduced mitochondrial membrane potential and NADH pools and higher redox indices, indicative of respiratory chain dysfunction. Increasing concentrations of ferutinin, a Ca2+ ionophore, led to oscillatory Ca2+ signals in fibroblasts resembling dynamic Ca2+ changes that occur during seizure-like activity. Co-monitoring of mitochondrial membrane potential (ΔΨm) changes induced by ferutinin showed accelerated membrane depolarisation and cell collapse in fibroblasts with mutations in the mitochondrial genome when compared to controls. Ca2+ flash photolysis using caged Ca2+ confirmed impaired Ca2+ handling in fibroblasts with mitochondrial mutations. Findings indicate that intracellular Ca2+ levels cannot be compensated during periods of hyperexcitability, leading to Ca2+ overload and subsequent cell death in mitochondrial diseases. |
| Databáze: | OpenAIRE |
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