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Review
. 2024 Sep 5:15:1469053.
doi: 10.3389/fphar.2024.1469053. eCollection 2024.

Unraveling the nexus of age, epilepsy, and mitochondria: exploring the dynamics of cellular energy and excitability

Wen Xie #  1 , Sushruta Koppula #  2 , Mayur B Kale  3 , Lashin S Ali  4 , Nitu L Wankhede  3 , Mohit D Umare  3 , Aman B Upaganlawar  5 , Ahmed Abdeen  6 , Elturabi E Ebrahim  7 , Mohamed El-Sherbiny  8   9 , Tapan Behl  10 , Bairong Shen  11 , Rajeev K Singla  1   12
Affiliations
Review

Unraveling the nexus of age, epilepsy, and mitochondria: exploring the dynamics of cellular energy and excitability

Wen Xie et al. Front Pharmacol. .

Abstract

Epilepsy, a complex neurological condition marked by recurring seizures, is increasingly recognized for its intricate relationship with mitochondria, the cellular powerhouses responsible for energy production and calcium regulation. This review offers an in-depth examination of the interplay between epilepsy, mitochondrial function, and aging. Many factors might account for the correlation between epilepsy and aging. Mitochondria, integral to cellular energy dynamics and neuronal excitability, perform a critical role in the pathophysiology of epilepsy. The mechanisms linking epilepsy and mitochondria are multifaceted, involving mitochondrial dysfunction, reactive oxygen species (ROS), and mitochondrial dynamics. Mitochondrial dysfunction can trigger seizures by compromising ATP production, increasing glutamate release, and altering ion channel function. ROS, natural byproducts of mitochondrial respiration, contribute to oxidative stress and neuroinflammation, critical factors in epileptogenesis. Mitochondrial dynamics govern fusion and fission processes, influence seizure threshold and calcium buffering, and impact seizure propagation. Energy demands during seizures highlight the critical role of mitochondrial ATP generation in maintaining neuronal membrane potential. Mitochondrial calcium handling dynamically modulates neuronal excitability, affecting synaptic transmission and action potential generation. Dysregulated mitochondrial calcium handling is a hallmark of epilepsy, contributing to excitotoxicity. Epigenetic modifications in epilepsy influence mitochondrial function through histone modifications, DNA methylation, and non-coding RNA expression. Potential therapeutic avenues targeting mitochondria in epilepsy include mitochondria-targeted antioxidants, ketogenic diets, and metabolic therapies. The review concludes by outlining future directions in epilepsy research, emphasizing integrative approaches, advancements in mitochondrial research, and ethical considerations. Mitochondria emerge as central players in the complex narrative of epilepsy, offering profound insights and therapeutic potential for this challenging neurological disorder.

Keywords: ageing; epigenetic modification; epilepsy; ketogenic diet; mitochondria targeted therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Mitochondrial Dysfunction in Epilepsy. ROS: Reactive oxygen species; ATP: Adenosine triphosphate.
FIGURE 2
FIGURE 2
Imbalances in mitochondrial fusion and fission dynamics.
FIGURE 3
FIGURE 3
Role of calcium in excitotoxicity. TCA: Tricarboxylic acid.
FIGURE 4
FIGURE 4
Calcium imbalance and Neuronal Excitability caused by mitochondrial disfunction. NMDA: N-Methyl D- Aspartate, ROS: Reactive Oxygen Species, ATP: Adenosine triphosphate, Na+/K+ ATPase: Sodium Potassium ATPase pump.
FIGURE 5
FIGURE 5
Therapeutic strategies targeting mitochondria in epilepsy.
See this image and copyright information in PMC

References

    1. Abramovici S., Bagić A. (2016). “Epidemiology of epilepsy,” in Handb clin neurol (Elsevier B.V.), 159–171. 10.1016/B978-0-12-802973-2.00010-0 - DOI - PubMed
    1. Abu Shelbayeh O., Arroum T., Morris S., Busch K. B. (2023). PGC-1α is a master regulator of mitochondrial lifecycle and ROS stress response. Antioxidants (Basel) 12, 1075. 10.3390/antiox12051075 - DOI - PMC - PubMed
    1. Aglawe M. M., Kale M. B., Rahangdale S. R., Kotagale N. R., Umekar M. J., Taksande B. G., Agmatine improves the behavioral and cognitive impairments associated with chronic gestational ethanol exposure in rats, Brain Res. Bull. 167 (2021) 37–47. 10.1016/j.brainresbull.2020.11.015 - DOI - PubMed
    1. Aguiar C. C. T., Almeida A. B., Araújo P. V. P., de Abreu R. N. D. C., Chaves E. M. C., do Vale O. C., et al. (2012). Oxidative stress and epilepsy: literature review. Oxid. Med. Cell. Longev. 2012, 795259. 10.1155/2012/795259 - DOI - PMC - PubMed
    1. Alberti P., Semperboni S., Cavaletti G., Scuteri A. (2022). Neurons: the interplay between cytoskeleton, ion channels/transporters and mitochondria. Cells 11, 2499. 10.3390/cells11162499 - DOI - PMC - PubMed

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