Mitochondrial complex I, also known as NADH dehydrogenase or NADH-Q reductase, consists of 45 structural subunits. Deficiency in mitochondrial complex I is associated with mutations in various structural subunits and assembly factors, resulting in a wide range of clinical manifestations, including LHON, infantile LS, MELAS, and epilepsy (56).

Among the core subunits of complex I, mutations in MT-ND3 and MT-ND5 are more common. Point mutations in MT-ND3, such as m.10191 T > C, m.10158 T > C, and m.10197G > A, have been widely studied. More than 30 patients with the MT-ND3 m.10191 T > C mutation have been reported, with approximately 90% developing epilepsy, typically between the ages of 8 and 10. Seizure types include focal motor, persistent focal, and generalized tonic–clonic seizures (57, 58).

EEG findings in patients with the MT-ND3 m.10191 T > C mutation typically display interictal focal epileptic discharges, sharp waves, spikes in certain areas, and extensive slow-wave activity, with sharp waves present in some brain regions (57, 59). Imaging often reveals LS-like changes, such as involvement of the basal ganglia, thalamus, and brainstem, in about 50% of patients, with some exhibiting white matter-dominant polyencephalic lesions (57).

The MT-ND3 m.10158 T > C mutation is occasionally associated with isolated and recurrent stroke-like seizures. These seizures typically occur in middle age or later, manifesting as generalized clonic seizures, persistent focal seizures, and visual sensitivity seizures (60). EEG has periodic slow and sharp waves (61). MRI findings usually indicate lesions in the posterior cortex of the supratentorial area (62).

The common MT-ND5 m.13513G > A mutation is linked to multiple syndromes, including LS, MELAS, MERRF, LHON, and MELAS-LS overlap syndrome (63, 64). Some patients with this mutation also experience seizures. Dermaut et al. reported that a patient with the MT-ND6 m.14487 T > C mutation presented with myoclonic seizures, generalized tonic–clonic seizures, decreased EEG background activity, spike waves, and multi-spike waves (65). Patients with NDUFV1 mutations may exhibit myoclonic seizures and absence seizures (66, 67). Seizures are also linked to mutations in nDNA genes, including NDUFS2, NDUFS4, NDUFS8, NDUFA1, and NDUFA8 (68–70).

Currently, there is no effective treatment for mitochondrial complex I deficiency. Clinical management primarily focuses on enhancing mitochondrial energy metabolism, increasing antioxidant capacity, providing nutritional support, and using ASMs to control seizures. Approximately 60% of patients with the MT-ND3 m.10191 T > C mutation survive into puberty or later, which is a better prognosis than other complex I-related gene defects. A report from Japan indicated that homologous expression of codon-optimized MT-ND3 in patients with MT-ND3 mutations can increase ATP production and improve mitochondrial function, showing promise as a potential new treatment strategy (71).

Mitochondrial complex II, also known as succinate dehydrogenase (SDH) or succinate-ubiquinone oxidoreductase (SQR), Comprises four structural subunits: SDHA, SDHB, SDHC, and SDHD, all encoded by nDNA. Additionally, four assembly factors, SDHAF1, SDHAF2, SDHAF3, and SDHAF4, are involved in its assembly and function (72). Clinical manifestations of complex II deficiency vary and include LS, leukoencephalopathy, optic nerve atrophy, and epilepsy. Among 61 patients with complex II deficiency reported by Fullerton et al., five had seizures (72).

Mutations in SDHA are the most common cause of complex II deficiency and are mainly associated with LS. Neurological symptoms include epileptic encephalomyopathy, external ophthalmoplegia, and myoclonic seizures (73). In one case of an SDHA mutation, the patient experienced focal and generalized seizures, with EEG findings showing nonspecific slow-wave activity and focal epileptic discharges (74). Another case presented with Lennox–Gastaut syndrome and highly irregular EEG patterns (75). Both cases demonstrated imaging features resembling LS.

Biallelic variations in SDHB frequently result in complex II deficiency. Approximately 10 patients with LS have been identified with pathogenic SDHB variations, most exhibiting neurodegenerative symptoms, seizures, and dystonia, with one patient showing heat sensitivity (72). The clinical manifestations of complex II deficiency related to SDHB mutations are similar to LS but typically do not involve the basal ganglia, which can help differentiate the two conditions (76).

A review by SiyingLin et al. identified six patients with SDHD mutations, four of whom experienced generalized tonic–clonic seizures, multifocal focal seizures, and myoclonic seizures (77). Of the four known SDH assembly factors, only mutations in SDHAF1 have been linked to complex II deficiency. Andreas et al. reported five patients with homozygous SDHAF1 mutations, all of whom had motor degeneration and spastic paraplegia, with only one patient experiencing seizures (78).

Since complex II deficiency is rarer than other mitochondrial diseases, limited reports exist on its treatment and prognosis. Riboflavin has been shown to improve clinical manifestations in patients with complex II deficiency, potentially preventing disease progression and even reversing symptoms. In particular, patients with riboflavin transporter deficiency may benefit from high-dose riboflavin therapy (up to 70 mg/kg/day) (79).

Mitochondrial complex III, also known as ubiquinone-cytochrome c reductase or cytochrome bc1 complex, consists of 11 structural subunits. Cytochrome b is encoded by mitochondrial DNA (mtDNA), while the remaining 10 subunits are encoded by nuclear DNA (nDNA). Additionally, BCS1L, TTC19, and UQCC2, encoded by nDNA, are involved in the assembly of complex III (80). The Leucine zipper EF-hand domain transmembrane protein 1 (LETM1) is located in the inner mitochondrial membrane and plays a critical role in regulating the synthesis of cytochrome b. Downregulation of LETM1 reduces MT-CYB expression and increases susceptibility to seizures (81).

Mutations in cytochrome b can manifest in skeletal muscle involvement, exercise intolerance, MELAS, LS, and seizures (82). Seizures in these cases may present as spastic seizures, status epilepticus, focal non-convulsive status epilepticus, or generalized tonic–clonic seizures (83, 84). Scott et al. described a patient with a cytochrome b mutation who exhibited both Parkinson’s syndrome and MELAS, along with status epilepticus and tonic–clonic seizures. EEG findings showed decreased background activity and occasional generalized epileptic discharges (85).

BCS1L mutations are the most common cause of complex III deficiency and are linked to GRACILE syndrome, Björstand syndrome, liver disease, encephalopathy, dyskinesia, and epilepsy. Neurological symptoms, such as dyskinesia and seizures, generally manifest after the age of 1 month, with an epilepsy incidence of 33%. Patients with the BCS1L c.232A > G mutation have typically developed GRACILE syndrome, although epilepsy is often absent (86). Erika et al. described a case of rapid progression in a patient with a BCS1L mutation, characterized by growth retardation, epileptic spasms, and frequent seizures in later stages. MRI findings showed involvement of the thalamus and supratentorial white matter (87). Helen et al. described a patient with a novel BCS1L mutation who had slower disease progression, presenting with myopathy, focal motor seizures, and optic nerve atrophy (88). Hikmat et al. reported that 6 out of 33 patients with BCS1L mutations had seizures (86).

Mutations in TTC19, UQCC2, and UQCRC2 are also associated with seizures. Patients with missense TTC19 mutations (c.971 T > C and c.554 T > C) may present with tonic seizures and refractory epilepsy (89). Patients with UQCC2 mutations may experience generalized seizures and status epilepticus, with EEG findings showing low-voltage activity (90, 91). There have also been reports suggesting that mutations in the UQCRC2 gene can lead to generalized seizures (80). MRI findings in patients with complex III defects vary widely. Some resemble those seen in LS, with focal and bilateral symmetrical lesions in the basal ganglia, thalamus, and brain stem, while others show brain atrophy or underdeveloped myelin.

There is no specific therapy for respiratory chain complex III deficiency. Treatment focuses on managing symptoms and slowing disease progression. In one case, clinical symptoms improved following treatment with vitamin K3 and vitamin C (92). Patients with TTC19 mutations often present with early psychomotor retardation, followed by progressive neurological decline and poor prognosis (89). The survival rate for patients with homozygous or compound heterozygous BCS1L c.232A > G mutations is significantly lower compared to patients with other BCS1L mutations, underscoring the importance of genotype–phenotype correlation, prognosis evaluation, and genetic counseling (86). Early disease onset is generally associated with faster progression and higher mortality.

Mitochondrial complex IV, also known as cytochrome c oxidase (COX), is the terminal enzyme in the electron transport chain. It comprises 14 subunits, with 3 encoded by mitochondrial DNA (mtDNA) and the remaining 11 by nuclear DNA (nDNA). Several nuclear-encoded assembly factors, including SURF1, SCO1, SCO2, COX10, COX15, and LRPPRC, are involved in the assembly of complex IV (93). Cytochrome c oxidase deficiency affects the brain, heart, and skeletal muscle, leading to disorders such as LS and cardiomyopathy (94).

SURF1 deficiency is a monogenic mitochondrial disorder and the most common cause of cytochrome c oxidase-deficient LS. Approximately 80% of SURF1 mutations are truncating, caused by abnormal splicing, frameshift deletions, or nonsense mutations. Clinical features include weight loss, dystonia, stunted growth, and epilepsy, with an epilepsy incidence of 33.3%, most commonly presenting as generalized tonic–clonic and myoclonic seizures (95). MRI findings often show LS-like features, with symmetrical necrotic lesions in the basal ganglia and brainstem (96). In comparison, patients with SCO2 mutations tend to have earlier-onset symptoms that progress more rapidly, including hypertrophic cardiomyopathy, dystonia, and seizures. EEG findings commonly show focal epileptic discharges in the central and temporal regions (97, 98). The COX15 p.R217W mutation is associated with lactic acidosis, ataxia, and hypotonia, with epilepsy occurring in 71.4% of cases. Status epilepticus has also been reported, though specific seizure types have not been well-documented. EEG findings typically include multifocal slow-wave discharge (99, 100).

In addition to mutations in assembly factor genes, mutations in the three COX subunits encoded by mtDNA are also linked to epilepsy. MT-CO1 mutations can lead to a wide range of seizure types, including myoclonic seizures associated with the m.6480G > A and m.6930G > A missense mutations (101, 102). The m.7402delC mutation can cause non-convulsive status epilepticus (102). The missense mutation m.7023G > A is associated with seizures such as mid-wind, generalized tonic–clonic, and focal seizures. Patients with the m.6489G > A mutation display persistent partial and myoclonic seizures, generalized tonic–clonic seizures, recurrent status epilepticus, and diffuse epileptic activity on EEG, often accompanied by significantly reduced background activity. MT-CO3 subunit mutations have been reported in patients with recurrent MELAS-like seizures (103).

In mammals, COX4 has two isoforms: COX4I1 and COX4I2. The COX4I1 c.454C > A missense mutation has been linked to infantile spasms, high EEG irregularity, and multifocal spikes (104).

Treatment options for mitochondrial complex IV deficiency are limited and vary depending on the specific mutation. Arginine may help alleviate stroke-like episodes in patients with COX-deficient MELAS, while coenzyme Q10 has shown promise in slowing disease progression in COX4I1 deficiency (16, 104). EPI-743, a coenzyme Q10 derivative, has been found to prevent disease progression and improve quality of life and motor function in some SURF1-related LS cases (105). Additional treatments, such as the Pan-PPAR agonist bezafibrate and the AMPK agonist AICAR, have shown the potential to partially restore COX function in human and animal models (106). Intrathecal delivery of an adeno-associated viral vector serotype 9 (AAV9)-human SURF1 (hSURF1) has effectively corrected biochemical abnormalities in mouse models of SURF1 deficiency (107). Emerging therapies such as mitochondrial biogenesis and gene replacement also hold promise for future treatment strategies.

Mitochondrial complex V, also known as ATP synthase, is essential for mitochondrial energy production and comprises two functional domains: F1 and F0. The F1 domain contains five subunits (α, β, γ, δ, and ε), while the F0 domain consists of subunits a, b, c, d, e, f, g, I, k, A6L, F6, and the oligomycin-sensitive protein (OSCP) (108). Subunit, an and A6L of the F0 domain, are encoded by the MT-ATP6 and MT-ATP8 genes in mtDNA, while the remaining subunits, along with assembly factors (ATP assembly factors 1 and 2), coupling factors (inhibitor IF1 and coupling factor B), and ATP synthase-related proteins (MLQ and DAPIT), are encoded by nDNA (109). Mutations in MT-ATP6, MT-ATP8, ATPAF2, TMEM70, and ATP5E can lead to complex V deficiencies.

MT-ATP6 mutations are the most common and widely studied causes of complex V deficiency, characterized by a reduction in ATP synthesis and basal oxygen consumption. This can lead to clinical manifestations such as ataxia, cognitive impairment, neuropathy, and epilepsy, with an incidence of 37%. MILS and NARP syndrome are associated with seizure rates of 86 and 44%, respectively, with generalized seizures being the most frequent type (110). Common mutations in MT-ATP6-related epilepsy include m.8993 T > G, m.8993 T > C, m.9032 T > C, m.9058A > G, and m.8921G > A (111–114). The m.8993 T > G mutation is particularly associated with a high incidence of generalized tonic–clonic, myoclonic, and progressive myoclonic seizures. EEGs in patients with this mutation typically show slow background activity and widespread sharp-slow complexes, making EEG a key tool for assessing disease severity In contrast, the m. 8,993 T > C mutation generally leads to milder symptoms and later onset, though it is still associated with generalized tonic–clonic seizures. Patients with the m.9032 T > C mutation may experience focal seizures, and EEG findings often show sharp waves in the central parietal region (115).

Mutations in MT-ATP8, such as m.8502A > T and m.8411A > G, have been identified in patients with epilepsy (116, 117). The former is closely associated with medial temporal lobe epilepsy, while the latter is linked to generalized tonic–clonic seizures. Mutations in ATP5F1E, ATPAF2, ATP5PO, and TMEM70, all encoded by nDNA, are also implicated in seizure disorders (108, 118, 119). Homozygous mutations in ATP5F1E (c.35A > G), which affect the ε subunit of the F1 domain, commonly result in generalized tonic–clonic seizures. A patient with an ATP5PO mutation encoding OSCP recently died from refractory status epilepticus, and a separate case involving a TMEM70 mutation also presented with status epilepticus (119).

Treatment for complex V deficiency is largely symptomatic, focusing on the use of coenzyme Q10, vitamin B1, and vitamin C. α-ketoglutarate and aspartic acid have shown potential in increasing mitochondrial substrate phosphorylation, thereby normalizing ATP levels in cells with the m.8993 T > G mutation and reducing cell death (120). N-acetylcysteine and dihydrolipoic acid also hold therapeutic potential for patients with the m.8993 T > G mutation (121).

Coenzyme Q (CoQ or ubiquinone) plays a crucial role in mitochondrial electron transfer, shuttling electrons from complex I or II to complex III. Coenzyme Q deficiency can be classified into primary and secondary forms based on etiology. Secondary CoQ deficiency is not directly related to the biosynthesis of CoQ, while primary CoQ deficiency results from mutations in genes responsible for CoQ biosynthesis. The Clinical manifestations are highly heterogeneous (122).

The CoQ biosynthesis pathway is complex and involves at least 15 genes, including PDSS1, COQ1-PDSS2, COQ2, COQ3, COQ4, COQ5, COQ6, COQ7, COQ8-ADCK3, COQ8-ADCK4, COQ9, COQ10a, COQ10b, FDX1L, and FDXR. Additionally, three other genes, ADCK1, ADCK2, and ADCK5, are also believed to play roles in CoQ biosynthesis (123). The incidence of primary CoQ10 deficiency is estimated at approximately 1 in 50,000, and while it can occur at any age, it is more common in children. When the central nervous system (CNS) is involved, the clinical phenotype is diverse, ranging from growth retardation and encephalopathy to intellectual disability and epilepsy. Several CoQ biosynthesis genes have been implicated in epilepsy including COQ1-PDSS2, COQ2, COQ4, COQ5, COQ6, COQ8-ADCK3, COQ8-ADCK4, and COQ9, with COQ2, COQ4, and COQ8-ADCK3 mutations being more frequently associated with seizures (124).

COQ4 mutations have the highest incidence of epilepsy, reaching up to 69%, with a higher prevalence among females. The age of onset ranges from birth to 9 years, and clinical symptoms may appear as early as the first week of life. These symptoms include growth retardation, epilepsy, skeletal muscle involvement, and cardiomyopathy (125). Seizure types include status epilepticus, myoclonic seizures, and focal seizures, with or without altered consciousness (126). EEG findings typically show reduced background activity and focal seizures, with occasional sharp waves, particularly in the left parietal region during REM sleep (127, 128).

Mutations in the COQ8A gene (also known as CABC1 or ADCK3) represent the most common form of primary coenzyme Q10 deficiency. Clinical manifestations include early-onset cerebellar ataxia, various motor disorders, cognitive impairment, motor intolerance, and epilepsy, which occurs in approximately 32% of cases. Epilepsy phenotypes associated with COQ8A mutations include focal seizures, generalized tonic–clonic seizures, myoclonic seizures, absence seizures, persistent partial epilepsy, and status epilepticus (129–132). EEG findings typically show frequent focal epileptic discharges and δ waves. During the interictal period, multi-spike wave or spike–wave rhythms are observed in the bioccipital region but may also be seen in the parietal, temporal, and frontal lobes. Some patients exhibit paroxysmal discharges in response to medium- and high-frequency (10-30 Hz) light stimulation (133). Cranial MRI frequently reveals cerebellar atrophy, though other regions may also be affected, including the brainstem and supratentorial areas such as the parietal and frontal insular lobes. Additionally, T2-weighted imaging often shows high signal intensity in the dentate nucleus and dorsal pons (129).

Primary CoQ deficiency was initially reported in association with COQ2 mutations, characterized by encephalopathy, cerebellar dysplasia, and epilepsy, with a seizure incidence of approximately 40%. Seizure types in COQ2 deficiency include focal seizures with altered consciousness, persistent partial seizures, myoclonic seizures, and status epilepticus (122, 134, 135).

Therapeutic response to coenzyme Q10 or its derivatives varies by genetic mutation. Patients with COQ4 mutations may benefit from coenzyme Q10 supplementation, while those with PDSS2, COQ8A, and COQ9 mutations tend to respond less effectively. For patients with COQ2 or COQ6 mutations, supplementation with 4-hydroxybenzoic acid (4-HBA) may enhance endogenous CoQ10 synthesis (136, 137). In preclinical studies, the antioxidant probucol has shown greater efficacy in treating renal and metabolic complications in PDSS2 mutant mice but compared to coenzyme Q10 supplementation (138), this treatment remains under investigation.

Cytochrome c (CytC) is a water-soluble protein encoded by Ndna and composed of 104 amino acid residues. Its primary function is to facilitate electron transport between complex III and complex IV in the mitochondrial electron transport chain. Additionally, CytC plays a crucial role in apoptosis induction (139). During seizures, the production of harmful substances in neurons can increase the permeability of the mitochondrial inner membrane. CytC is subsequently released into the cytoplasm, where it binds to apoptosis-related factor 1(Apaf-1), promoting the formation of apoptotic bodies by binding with caspase-9. This process activates other caspases, leading to neuronal apoptosis. Mitochondrial damage exacerbates the susceptibility to seizures, creating a vicious circle that promotes further neuronal damage (140). Luan et al. found that a ketogenic diet can reduce the release of cytochrome c, thus playing a neuroprotective role (141).