Mitochondria fulfill this energy demand by generating ATP through oxidative phosphorylation. This process entails the transfer of electrons across several protein complexes within the inner membrane of mitochondria, ultimately leading to ATP synthesis (Xavier et al., 2016; Umare et al., 2021). Notably, neurons exhibit diverse energy demands based on their activity levels and location within the brain. Synaptic terminals, for instance, require rapid ATP production to support neurotransmission. Mitochondria are strategically positioned at synapses to meet this need promptly. Moreover, during increased neuronal activity, mitochondria move along axons and dendrites to the sites of higher energy consumption, ensuring a continuous energy supply (Tiwari et al., 2021; Brown et al., 2006).

Calcium ions (Ca²⁺) are pivotal in neuronal signaling and neurotransmitter release. Maintaining precise control over intracellular calcium concentrations is essential to prevent excessive excitability and excitotoxicity (Beal, 1995; Gibson et al., 2010). When neurons experience increased calcium influx, as occurs during neurotransmission, mitochondria buffer excess calcium ions, preventing their accumulation in the cytosol (Rharass et al., 2014; Panov et al., 2002). This buffering action helps dampen excitatory signals and leads to synaptic event termination (D’Angelo et al., 2023). Moreover, mitochondria sequester calcium within their matrix, where it can be safely stored and released as needed. This calcium-handling capability of mitochondria is particularly relevant in the context of epilepsy. Dysfunctional mitochondria can lead to disrupted calcium regulation, potentially resulting in heightened neuronal excitability and an increased susceptibility to seizures (Matuz-Mares et al., 2022). Wide harmful events, including elevated ROS generation and abnormalities in the control of intracellular calcium concentrations, have been linked to a critical role for mitochondria in aging-related diseases. These events have been linked to mPTP activation, which has significant implications for cell viability. Consequently, mPTP becomes a viable strategy for neuroprotection in neurodegenerative disorders associated with aging (Baev et al., 2022; Pivovarova and Andrews, 2010; Baev et al., 2024).

Cells can adjust and operate in a constantly evolving cellular setting by establishing interaction among organelles. At particular locations known as mitochondria-associated membranes (MAMs), ER and mitochondria combine to regulate several cellular processes, like lipid generation and transfer, apoptosis, mitochondrial dynamics, and calcium signaling (Saneto and Perez, 2022). Furthermore, these activities are notably impacted early in the pathophysiology of neurodegenerative conditions, indicating a potential role for MAMs in the etiology of these conditions (Kim et al., 2022).

Mitochondrial dysfunction has emerged as a compelling contributor to the genesis of seizures in epilepsy. This subsection delves into the intricate mechanisms through which impaired mitochondrial function can fuel hyperexcitability and provide a fertile ground for seizure initiation (Shin et al., 2011).

ROS are decidedly reactive molecules that contain free radicals like superoxide (O₂ ⁻) and hydrogen peroxide (H₂O₂). They are natural byproducts of various cellular processes, including mitochondrial respiration. While ROS plays vital roles in cell signaling and immune defense under normal circumstances, an excessive build-up of ROS, often associated with mitochondrial dysfunction, can have profound implications for epileptogenesis, leading to epilepsy (Upaganlawar et al., 2021; Waldbaum and Patel, 2010a; Dong et al., 2009).

Mitochondrial dynamics involve two opposing processes: fusion and fission (Picca et al., 2021; Lee and Yoon, 2016). Mitochondrial fusion merges individual mitochondria into a single, interconnected network. This mechanism facilitates the transfer of mitochondrial contents, such as proteins and DNA, promoting the mingling of healthy and impaired mitochondria. Fusion additionally supports the preservation of an optimal mitochondrial membrane potential and the restoration of damaged mitochondrial DNA. It ensures a uniform mitochondrial population, vital for effective energy generation and calcium regulation (Chakravorty et al., 2019; Suen et al., 2008; Wankhede et al., 2022). Mitochondrial Fission, conversely, partitions mitochondria into smaller organelles. This mechanism is vital for quality control, enabling the segregation and elimination of impaired or dysfunctional mitochondria. Fission also aids in distributing mitochondria to regions with elevated energy requirements, such as synaptic terminals (Chen et al., 2023). Collectively, fusion and fission uphold a dynamic balance of mitochondrial structure and function, pivotal for cellular homeostasis (Badole et al., 2021; Suárez-Rivero et al., 2017).

Recent findings indicate disruptions in mitochondrial dynamics in epilepsy. These disruptions can carry substantial implications for neuronal wellbeing and excitability. Investigations using animal models of epilepsy and postmortem brain tissue from epilepsy patients have unveiled discrepancies in the regulation of mitochondrial fusion and fission dynamics (Olkhova et al., 2023). In certain instances, an abundance of fission occurs, resulting in fragmented mitochondria, whereas in other cases, fusion prevails, yielding elongated, interconnected networks. These imbalances can interfere with mitochondrial quality control, impede the elimination of impaired mitochondria, and undermine overall mitochondrial function (Kundap et al., 2020). Further, proper mitochondrial trafficking along axons and dendrites is essential for meeting the energy demands of specific neuronal regions (Chang and Reynolds, 2006; Gao et al., 2017; Schwarz, 2013). Changes in fusion-fission dynamics can disturb mitochondrial trafficking, leading to irregular distribution and compromised energy supply to vital regions. This disparity in mitochondrial distribution might contribute to heightened neuronal hyperexcitability, a characteristic feature of epilepsy (Reddy et al., 2011; Bossy-Wetzel et al., 2008; Chen and Chan, 2009). Altered mitochondrial dynamics can also affect calcium regulation within neurons. Mitochondria participate in buffering intracellular calcium levels, and disruptions in fusion and fission events can lead to imbalances in calcium handling. Elevated intracellular calcium concentrations can enhance neuronal excitability, making neurons more susceptible to seizures (Figure 2).

The interaction between mitochondrial dynamics and epilepsy represents a multifaceted area of investigation, drawing increasing attention within the field of epilepsy research. Neurons, known for their voracious energy demands, depend heavily on the finely tuned orchestration of mitochondrial dynamics to maintain essential cellular processes. In the context of epilepsy, these dynamics play a pivotal yet intricate role in seizure propagation (Suárez-Rivero et al., 2017). Age-related disorders and aging have been consistently linked to aberrant mitochondrial architecture, suggesting that cellular dynamics are degraded with cellular aging (Bhatti et al., 2017). Several investigations indicate that mitochondrial activity effectively regulates the aging process in addition to pathological conditions. Moreover, alterations to the structure or function of mitochondria can directly impact an organism’s lifetime (Guo et al., 2022).

Despite its relatively small size, the brain is a remarkably energy-intensive organ, consuming a disproportionate amount of the body’s total energy. Neurons, in particular, are voracious energy consumers due to their constant electrical activity, neurotransmitter synthesis and release, and the maintenance of ion gradients across their membranes. Epileptic seizures represent a state of heightened neuronal activity characterized by repetitive and synchronized firing of neurons. This heightened activity places substantial metabolic demands on the brain. The energy demands during seizures are primarily met through the ATP generated by the mitochondria (Vergara et al., 2019).

During seizures, neurons experience a surge in energy demands, primarily to support the multiple processes. Neurons rely on energy-consuming ion pumps, such as the sodium-potassium pump (Na+/K+ pump), to maintain ion gradients across their membranes. These ion gradients are essential for normal neuronal excitability and neurotransmission (Zsurka and Kunz, 2015). During seizures, the Na+/K+ pump works overtime to restore membrane potential, consuming considerable ATP. Additionally, the repetitive firing of action potentials during seizures demands substantial energy. Each action potential requires the active transport of ions across the neuronal membrane, which is energetically costly. Further, releasing neurotransmitters, such as glutamate and GABA, is energy-intensive (Kann and Kovács, 2007; Zsurka and Kunz, 2015; Taksande et al., 2017). These neurotransmitters are packaged into synaptic vesicles and released into the synaptic cleft during neuronal communication. The postsynaptic response to neurotransmitter release involves the activation of ion channels, such as NMDA receptors, which are critical for synaptic plasticity and excitatory neurotransmission. These receptor activations are energy-dependent. Epileptic seizures dramatically increase the energy demands of neurons due to the heightened electrical activity and neurotransmission (Sumadewi et al., 2023). These demands are met primarily through mitochondrial ATP production (Badole et al., 2021; Tiwari et al., 2021; Upaganlawar et al., 2021; Kim et al., 2020).

Mitochondria play a pivotal role in meeting the heightened energy demands of seizures by serving as the primary ATP generators within neurons. Mitochondria exhibit flexibility in utilizing substrates for ATP production. During seizures, the brain resorts to anaerobic glycolysis as an alternative energy source, producing lactate. Subsequently, mitochondria can convert lactate back into pyruvate and employ it for oxidative phosphorylation. This lactate-pyruvate shuttle is essential for sustaining energy production during prolonged seizures (Zsurka and Kunz, 2015). It plays a pivotal role in buffering intracellular calcium levels during seizures. The excessive calcium influx into neurons can lead to excitotoxicity. Mitochondria, with their ability to sequester calcium within their matrix, help prevent this calcium-induced neuronal damage. This calcium buffering is energy-dependent and relies on the electrochemical gradient maintained by mitochondria (Kovac et al., 2017). Mitochondria also contribute to redox balance, which is essential during seizures. The production of ROS is elevated during heightened neuronal activity. Mitochondria are both sources and targets of ROS. They can produce ROS as natural byproducts of respiration, but they also have antioxidant defenses to mitigate oxidative stress. Maintaining this delicate balance is crucial for cellular health during seizures (Umare et al., 2021).

Neurons have an impressive array of ion channels that meticulously regulate their excitability. These channels fall into several categories, each with unique properties and functions.

Mitochondria exert a multifaceted influence on neuronal excitability through their intricate interactions with ion channels. Firstly, they serve as the primary energy suppliers, generating ATP through oxidative phosphorylation, which is essential for operating ion pumps like the sodium-potassium (Na⁺/K⁺) pump (Baev et al., 2022). Reduced mitochondrial ATP production can disrupt ion balance, leading to neuronal hyperexcitability (Clemente-Suárez et al., 2023). Secondly, mitochondria act as vital regulators of intracellular calcium levels, efficiently buffering elevated calcium concentrations that can activate calcium-sensitive ion channels, including calcium-activated potassium (KCa) channels. This calcium buffering function helps maintain proper ion channel activity and prevents aberrant neuronal excitability (Kann and Kovács, 2007; Kovac et al., 2017; V Frolov et al., 2016). Lastly, mitochondria are a significant source of ROS, which plays a role in redox signaling. ROS can directly modulate ion channel function, inducing changes in neuronal excitability, thus contributing to the intricate interplay between mitochondria and ion channels in regulating neuronal activity and excitability (Umare et al., 2021; V Frolov et al., 2016).

Epigenetic modifications play a critical role in regulating gene expression concerning mitochondrial function. These modifications, including DNA methylation, histone modifications, and non-coding RNAs, intricately shape the epigenetic environment, controlling the expression of genes associated with mitochondrial biogenesis, metabolism, and function. In epilepsy, disruptions in these epigenetic patterns are increasingly acknowledged as factors contributing to the abnormal neuronal excitability observed during seizures (Henshall and Kobow, 2015). DNA methylation, which entails adding methyl groups to cytosine residues in CpG dinucleotides, can directly impact mitochondrial function by regulating the expression of genes responsible for encoding mitochondrial proteins (Dostal and Churchill, 2019). For example, hypermethylation of the PGC-1α gene, a master regulator of mitochondrial biogenesis and function, has been linked to reduced mitochondrial density and compromised oxidative metabolism in epilepsy (Abu Shelbayeh et al., 2023). Histone modifications (acetylation, methylation, and phosphorylation) regulate chromatin structure and gene expression. In epilepsy, changes in histone acetylation and methylation patterns have been linked to alterations in gene expression, particularly those governing ion channel regulation and synaptic transmission. Significantly, these histone modifications can indirectly affect mitochondrial function by influencing the expression of nuclear-encoded mitochondrial genes, thereby impacting mitochondrial biogenesis and oxidative capacity (Boison and Rho, 2020). Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have become vital regulators in epigenetic processes. In epilepsy, dysregulation of miRNAs directly affects mitochondrial genes, leading to compromised mitochondrial function, reduced ATP production, and increased oxidative stress levels. Moreover, lncRNAs have been demonstrated to influence mitochondrial dynamics and bioenergetics by interacting with nuclear-encoded mitochondrial genes, thereby introducing additional complexity to the epigenetic control of mitochondrial activity (Catanesi et al., 2020; Wang and Zhao, 2021). In summation, epigenetic modifications profoundly impact mitochondrial function through diverse mechanisms, revealing their central role in the molecular intricacies of epileptogenesis and offering potential avenues for therapeutic intervention aimed at restoring mitochondrial function and mitigating the hyperexcitability characteristic of epilepsy.

The intricate interplay between epigenetics and epilepsy has illuminated a multifaceted landscape of molecular mechanisms driving epileptogenesis, with profound implications for mitochondrial involvement. Epilepsy, characterized by recurrent seizures and abnormal neuronal excitability, has increasingly been linked to epigenetic alterations, such as DNA methylation, histone modifications, and non-coding RNA expression. These epigenetic modifications exert far-reaching effects on gene expression patterns within neurons, influencing the expression of genes directly associated with mitochondrial function and homeostasis (Henshall and Kobow, 2015; Boison and Rho, 2020). In epilepsy, such epigenetic modifications can lead to mitochondrial dysfunction through various avenues, profoundly affecting neuronal excitability. One notable consequence is metabolic reprogramming, where altered epigenetic patterns steer neuronal energy metabolism away from oxidative phosphorylation and towards glycolysis. This metabolic shift diminishes mitochondrial ATP production, depriving neurons of the energy required for ion pump operation and overall excitability regulation. Moreover, epigenetically induced mitochondrial dysfunction contributes to increased production of ROS, exacerbating oxidative stress and further perturbing mitochondrial membrane integrity and electron transport chain function (Bhatti et al., 2017). This cascade of events significantly contributes to neuronal hyperexcitability, a hallmark of epilepsy.

Furthermore, epigenetic regulation extends to mitochondrial biogenesis, impacting mitochondrial density and function. Altered DNA methylation and histone modifications can either promote or hinder mitochondrial biogenesis, affecting the capacity for energy production and calcium buffering and thereby influencing neuronal excitability (Henshall and Kobow, 2015; Jiang et al., 2008; Van Vliet et al., 2007). Additionally, epigenetic changes can directly influence ion channel expression, disrupting ion homeostasis and membrane potential, ultimately promoting hyperexcitability and lowering the seizure threshold (Qureshi and Mehler, 2010). Collectively, these intricate interactions underscore the vital role of epigenetics in the pathophysiology of epilepsy and its direct implications for mitochondrial involvement. Understanding these molecular intricacies offers promising avenues for therapeutic intervention in epilepsy, with strategies aimed at restoring mitochondrial function and mitigating the aberrant neuronal excitability that characterizes this neurological disorder.

Mitochondria-targeted antioxidants represent a promising therapeutic approach for addressing mitochondrial dysfunction and oxidative stress in epilepsy. These compounds are designed to accumulate within the mitochondria, where they can neutralize ROS and protect mitochondrial components from oxidative damage. The rationale behind using mitochondria-targeted antioxidants in epilepsy is their potential to mitigate the harmful effects of excessive ROS production, a common feature of mitochondrial dysfunction in this neurological disorder (Umare et al., 2021). Mitochondria-targeted antioxidants typically contain an antioxidant molecule linked to a lipophilic cation, allowing them to accumulate selectively in the mitochondria due to the organelle’s negative membrane potential. Once inside the mitochondria, these antioxidants scavenge ROS, including superoxide and hydrogen peroxide, which are natural byproducts of oxidative phosphorylation (Yang et al., 2020; Mukhopadhyay et al., 2012). Firstly, they play a crucial role in reducing oxidative stress within the mitochondria, effectively curbing the accumulation of ROS. This reduction in oxidative stress is instrumental in mitigating mitochondrial dysfunction, thereby preserving the organelle’s pivotal functions in ATP production and calcium buffering. Secondly, these antioxidants contribute to neuroprotection by safeguarding mitochondrial integrity. In epilepsy, where seizures and oxidative stress often lead to neuronal damage and cell death, the preservation of mitochondria’s structural and functional integrity offers a promising strategy for shielding neurons from seizure-induced injury (Waldbaum and Patel, 2010a; Waldbaum and Patel, 2010b). Lastly, mitochondria-targeted antioxidants may indirectly influence neuronal excitability by maintaining ion channel function and cellular energy balance. This modulation of excitability, stemming from the preservation of mitochondrial function and reduction in oxidative stress, can potentially decrease the likelihood of seizure initiation and propagation (Apostolova and Victor, 2015). Collectively, these diverse benefits underscore the therapeutic potential of mitochondria-targeted antioxidants in managing epilepsy, addressing the symptoms and underlying cellular and molecular mechanisms contributing to this neurological disorder (Table 1).

Modulation of mitochondrial dynamics represents an emerging strategy for seizure control in epilepsy (Cardoso et al., 2022). Therapeutic interventions aimed at restoring proper mitochondrial dynamics hold promise for mitigating seizure activity (Luo et al., 2020). Promoting mitochondrial fusion can enhance the organelle’s bioenergetic capacity and calcium buffering capabilities, potentially raising the seizure threshold (Uittenbogaard and Chiaramello, 2014). Conversely, encouraging mitochondrial fission may facilitate the removal of damaged mitochondria, reducing the generation of reactive oxygen species and oxidative stress, both associated with epileptogenesis (Chen et al., 2012). While the field of mitochondrial dynamics modulation for seizure control is still in its infancy, it offers an intriguing avenue for the development of innovative epilepsy therapies targeting the very core of mitochondrial dysfunction underlying this neurological condition.

The ketogenic diet and related metabolic therapies have garnered substantial attention for their potential in managing epilepsy, particularly drug-resistant forms. The ketogenic diet is characterized by high-fat, low-carbohydrate, and moderate-protein intake, which induces a metabolic shift in the body, producing ketone bodies as an alternative energy source (Shaaban et al., 2023). Ketone bodies, such as beta-hydroxybutyrate, acetoacetate, and acetone, have been shown to exert neuroprotective effects, modulate neuronal excitability, and enhance mitochondrial function (Yang et al., 2019). These metabolic changes may help raise the seizure threshold and reduce seizure frequency in some individuals with epilepsy. Other metabolic therapies, including the modified Atkins diet and medium-chain triglyceride (MCT) oil supplementation, offer variations of the ketogenic approach, providing flexibility in dietary management (D’Andrea Meira et al., 2019; Borowicz-Reutt et al., 2024).While the mechanisms underlying the antiepileptic effects of these therapies are not fully understood, they likely involve a combination of factors, including increased mitochondrial efficiency, reduced oxidative stress, and altered neurotransmitter metabolism. Although the ketogenic diet and metabolic therapies may not be suitable for all epilepsy patients, they represent valuable adjunctive options, especially for those with drug-resistant epilepsy, offering a non-pharmacological approach to seizure control and improved quality of life.