Mitochondria, oxidative stress, and temporal lobe epilepsy

Abstract

Mitochondrial oxidative stress and dysfunction are contributing factors to various neurological disorders. Recently, there has been increasing evidence supporting the association between mitochondrial oxidative stress and epilepsy. Although certain inherited epilepsies are associated with mitochondrial dysfunction, little is known about its role in acquired epilepsies such as temporal lobe epilepsy. Mitochondrial oxidative stress and dysfunction are emerging as key factors that not only result from seizures, but may also contribute to epileptogenesis. The occurrence of epilepsy increases with age, and mitochondrial oxidative stress is a leading mechanism of aging and age-related degenerative disease, suggesting a further involvement of mitochondrial dysfunction in seizure generation. Mitochondria have critical cellular functions that effect neuronal excitability including production of adenosine triphosphate (ATP), fatty acid oxidation, control of apoptosis and necrosis, regulation of amino acid cycling, neurotransmitter biosynthesis, and regulation of cytosolic Ca2+ homeostasis. Mitochondria are the primary site of reactive oxygen species (ROS) production making them uniquely vulnerable to oxidative stress and damage which can further affect cellular macromolecule function, the ability of the electron transport chain to produce ATP, antioxidant defenses, mitochondrial DNA stability, and synaptic glutamate homeostasis. Oxidative damage to one or more of these cellular targets may affect neuronal excitability and increase seizure susceptibility. The specific targeting of mitochondrial oxidative stress, dysfunction, and bioenergetics with pharmacological and non-pharmacological treatments may be a novel avenue for attenuating epileptogenesis and seizure initiation.

The Cross-Talk Between Mitochondria and the Nucleus in the Response to Oxidative Stress Associated with Mitochondrial Dysfunction in Mitochondrial Encephalomyopathies

“…Taken together, the increase of oxidative stress and oxidative damage and the dysregulation of antioxidant enzymes are involved in the deterioration of bioenergetic function of the affected tissues, especially in the brain and skeletal muscle from patients with mitochondrial encephalomyopathies, which depend on mitochondrial function for supply of most of the ATP (Wei & Lee, 2003). Recent studies conducted in our own and other laboratories have provided compelling evidence to support the notion that oxidative stress elicited by impairment of the respiratory chain in the affected tissues of patients plays a role in the pathogenesis and progression of mitochondrial diseases and seizure generation (Waldbaum et al, 2010a;.…”

Can antioxidants compliment for the degrading conditions in epilepsy

“…The continuation of such process may lead to cell apoptosis. Similar deficiencies of oxidative phosphorylationhas been studied in epileptogenic brain regions of therapy-resistant focal epilepsies, such temporal lobe epilepsy with Ammon's horn sclerosis [5]. Seizures develop due to ROS under some pathophysiological conditions and seizure-induced neurodegeneration.…”

Mitochondria Function in Diabetes – From Health to Pathology – New Perspectives for Treatment of Diabetes-Driven Disorders

“…Oxidative damage especially affects the mitochondrial electron transport chain and, when the ETC enzymes stop working properly, the ROS production increases. This may result in the incomplete oxygen consumption, reduced production of ATP, and finally overproduction of ROS (Waldbaum & Patel, 2009). …”

“…3) (Duchen, 2004, Borutaite, 2010. The outer membrane contains porins, which make it permeable to molecules smaller than 5-6 kDa (Waldbaum & Patel, 2009). Compounds such as water, O 2 , CO 2 , and NH 3 easily pass through the membrane, but hydrophilic metabolites and all inorganic ions in order to get over this membrane require the participation of specific channels and carrier proteins.…”

“…pyruvate dehydrogenase, or metabolic rate. These organelles participate in biosynthesis of amino acids, vitamin cofactors, fatty acids and neurotransmitters (Waldbaum & Patel, 2009). Many other biochemical reactions are associated with the functioning of these structures, including synthesis of heme group and some steps of steroid synthesis.…”