Mitochondrial dysfunction in epilepsy

Folbergrová, Jaroslava; Kunz, Wolfram S.

doi:10.1016/j.mito.2011.04.004

Cited by 148 publications

(101 citation statements)

References 88 publications

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“…(1) neuronal hyperexcitability, which suggests the presence of an "intracellular ion disturbance" (sodium, potassium and calcium) triggering an abnormal threshold in the action potential of the neuronal membrane that could lead to changes in the pattern of the neuronal excitability and synaptic transmission in some areas of the brain tissue 10,11 . (2) neuronal loss, which suggests that a "mitochondrial cytopathy" triggers an energy failure in some areas of the brain causing neuronal death 10,11 .…”

Section: What Is the Pathogenesis?mentioning

confidence: 99%

“…(2) neuronal loss, which suggests that a "mitochondrial cytopathy" triggers an energy failure in some areas of the brain causing neuronal death 10,11 . However, neither of these hypotheses alone could explain comprehensively all of major disease manifestations in MERRF patients, and similar presentations can occur in other mitochondrial diseases.…”

Section: What Is the Pathogenesis?mentioning

confidence: 99%

“…However, neither of these hypotheses alone could explain comprehensively all of major disease manifestations in MERRF patients, and similar presentations can occur in other mitochondrial diseases. The formation of ATP in mitochondria is essential for both the excitability and self preservation of the neuron 10,11 . Thus, the mechanisms that trigger the main manifestations are correlated with a combination of neuronal loss and hyperexcitability dysfunction, perhaps both, initiated by the failure of oxidative phosphorylation in specific areas of the brain tissue, and they may be responsible for the pathogenesis of the major clinical manifestations of MERRF patients (Figure 2) 10,11 .…”

Section: What Is the Pathogenesis?mentioning

confidence: 99%

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When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

Lorenzoni

Scola

Kay

et al. 2014

Arq. Neuro-Psiquiatr.

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Myoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disorder. Diagnostic criteria for MERRF include typical manifestations of the disease: myoclonus, generalized epilepsy, cerebellar ataxia and ragged red fibers (RRF) on muscle biopsy. Clinical features of MERRF are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNA Lys gene of the DNAmt, mainly A8344G, are responsible for almost 90% of MERRF cases. Morphological changes seen upon muscle biopsy in MERRF include a substantive proportion of RRF, muscle fibers showing a deficient activity of cytochrome c oxidase (COX) and the presence of vessels with a strong reaction for succinate dehydrogenase and COX deficiency. In this review, we discuss mainly clinical and laboratory manifestations, brain images, electrophysiological patterns, histology and molecular findings as well as some differential diagnoses and treatments.Keywords: MERRF, mitochondrial, epilepsy, myoclonus, myopathy. RESUMOEpilepsia mioclônica associada com fibras vermelhas rasgadas (MERRF) é uma rara doença mitocondrial. O critério diagnóstico para MERRF inclui as manifestações típicas da doença: mioclonia, epilepsia generalizada, ataxia cerebelar e fibras vermelhas rasgadas (RRF) na biópsia de músculo. Na fase inicial da doença, as manifestações clínicas podem não ser uniformes, e correlação entre as manifestações clínicas e fisiopatologia não estão completamente elucidadas. Estima-se que as mutações de ponto no gene tRNA Lys do DNAmt, principalmente a A8344G, sejam responsáveis por quase 90% dos casos de MERRF. As alterações morfológicas na biópsia muscular incluem uma grande proporção de RRF, fibras musculares com deficiência de atividade da citocromo c oxidase (COX) e presença de vasos com forte reação para succinato desidrogenase e deficiência da COX. Nesta revisão, são discutidas as principais manifestações clínicas e laboratoriais, imagens cerebrais, padrões eletrofisiológicos, histológicos e alterações moleculares, bem como, alguns dos diagnósticos diferenciais e tratamentos.

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Section: What Is the Pathogenesis?mentioning

confidence: 99%

Section: What Is the Pathogenesis?mentioning

confidence: 99%

Section: What Is the Pathogenesis?mentioning

confidence: 99%

See 1 more Smart Citation

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

Lorenzoni

Scola

Kay

et al. 2014

Arq. Neuro-Psiquiatr.

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“…It is hypothesized that oxidative damage of mtDNA due to febrile seizures in childhood could be the reason for increased mutagenesis. A slow clonal expansion of these deletions would then lead to respiratory dysfunctions in hippocampal pyramidal neurons and interneurons causing cell death and intractable chronic epilepsy at adult age (54,84). Clonal expansions of mtDNA deletions have also been observed in patients with multiple sclerosis (MS) and are suggested to be an important contributor to neurodegeneration in MS (85,86).…”

Section: Figmentioning

confidence: 99%

Mitochondrial involvement in neurodegenerative diseases

Kunz

2013

IUBMB Life

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The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis.Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions. V C 2013 IUBMB Life, 65(3): [263][264][265][266][267][268][269][270][271][272] 2013

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“…In turn, we can raise the third data-driven hypothesis for further research that LPS action in the brain has a synaptic effect, targeting the synaptic molecular network and inducing a rapid onset change in neurotransmission elicited by immune response related cytokine level elevation. This is an interesting hypothesis for further research because synaptic mitochondria are involved in seizure genesis (Folbergrová and Kunz, 2012).…”

Section: Proteomics Data Highlights Proteins That Are Also Involved Imentioning

confidence: 94%

Brain protein expression changes in WAG/Rij rats, a genetic rat model of absence epilepsy after peripheral lipopolysaccharide treatment

Győrffy

Kovács

Gulyássy

et al. 2014

Brain, Behavior, and Immunity

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a b s t r a c tPeripheral injection of bacterial lipopolysaccharide (LPS) facilitates 8-10 Hz spike-wave discharges (SWD) characterizing absence epilepsy in WAG/Rij rats. It is unknown however, whether peripherally administered LPS is able to alter the generator areas of epileptic activity at the molecular level. We injected 1 mg/kg dose of LPS intraperitoneally into WAG/Rij rats, recorded the body temperature and EEG, and examined the protein expression changes of the proteome 12 h after injection in the frontoparietal cortex and thalamus. We used fluorescent two-dimensional differential gel electrophoresis to investigate the expression profile. We found 16 differentially expressed proteins in the fronto-parietal cortex and 35 proteins in the thalamus. It is known that SWD genesis correlates with the transitional state of sleep-wake cycle thus we performed meta-analysis of the altered proteins in relation to inflammation, epilepsy as well as sleep. The analysis revealed that all categories are highly represented by the altered proteins and these protein-sets have considerable overlap. Protein network modeling suggested that the alterations in the proteome were largely induced by the immune response, which invokes the NFkB signaling pathway. The proteomics and computational analysis verified the known functional interplay between inflammation, epilepsy and sleep and highlighted proteins that are involved in their common synaptic mechanisms. Our physiological findings support the phenomenon that high dose of peripheral LPS injection increases SWD-number, modifies its duration as well as the sleep-wake stages and decreases body temperature.

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Mitochondrial dysfunction in epilepsy

Cited by 148 publications

References 88 publications

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

Mitochondrial involvement in neurodegenerative diseases

Brain protein expression changes in WAG/Rij rats, a genetic rat model of absence epilepsy after peripheral lipopolysaccharide treatment

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