UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Impaired Bioenergetics in Mutant Mitochondrial DNA Determines Cell Fate During Seizure-Like Activity

Kovac, S; Preza, E; Houlden, H; Walker, MC; Abramov, AY; (2019) Impaired Bioenergetics in Mutant Mitochondrial DNA Determines Cell Fate During Seizure-Like Activity. Molecular Neurobiology , 56 (1) pp. 321-334. 10.1007/s12035-018-1078-9. Green open access

[thumbnail of SKovac_.pdf]
Preview
Text
SKovac_.pdf - Accepted Version

Download (1MB) | Preview

Abstract

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.

Type: Article
Title: Impaired Bioenergetics in Mutant Mitochondrial DNA Determines Cell Fate During Seizure-Like Activity
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s12035-018-1078-9
Publisher version: http://dx.doi.org/10.1007/s12035-018-1078-9
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Ca2+, Epilepsy, Fibroblasts, Mitochondrial mutation, PTP opening
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10048680
Downloads since deposit
198Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item