The role of oxidative stress in glaucoma

DNA damage is related to a variety of degenerative diseases such as cancer, atherosclerosis and neurodegenerative diseases, depending on the tissue affected. Increasing evidence indicates that reactive oxygen species (ROS) play a key role in the pathogenesis of primary open angle glaucoma (POAG), the main cause of irreversible blindness worldwide. Oxidative DNA damage is significantly increased in the ocular epithelium regulating aqueous humor outflow, i.e., the trabecular meshwork (TM), of glaucomatous patients compared to controls. The pathogenic role of ROS in glaucoma is supported by various experimental findings, including (a) resistance to aqueous humor outflow is increased by hydrogen peroxide by inducing TM degeneration; (b) TM possesses remarkable antioxidant activities, mainly related to superoxide dismutase-catalase and glutathione pathways that are altered in glaucoma patients; and (c) intraocular-pressure increase and severity of visual-field defects in glaucoma patients parallel the amount of oxidative DNA damage affecting TM. Vascular alterations, which are often associated with glaucoma, could contribute to the generation of oxidative damage. Oxidative stress, occurring not only in TM but also in retinal cells, appears to be involved in the neuronal cell death affecting the optic nerve in POAG. The highlighting of the pathogenic role of ROS in POAG has implications for the prevention of this disease as indicated by the growing number of studies using genetic analyses to identify susceptible individuals and of clinical trials testing the efficacy of antioxidant drugs for POAG management.     

Senescent phenotype of trabecular meshwork cells displays biomarkers in primary open-angle glaucoma

Glaucoma is a major cause of irreversible blindness, affecting more than 70 million individuals worldwide. Elevated intraocular pressure (IOP) is a major risk factor in the development of glaucoma and in the progression of glaucomatous damage. High IOP usually occurs as a result of an increase in aqueous humor outflow resistance in trabecular meshwork (TM). Primary open angle glaucoma (POAG) is characterized by quantifiable parameters including the IOP, the aqueous outflow facility, and geometric measurements of the optic disc and visual defects. Morphological and biochemical analyses of the TM of POAG patients revealed loss of cells, increased accumulation of extracellular matrix (ECM), changes in the cytoskeleton, cellular senescence and the process of subclinical inflammation. Various biochemical and molecular biology biomarkers of TM cells senescence are considered in the article. Oxidative stress is becoming an important factor more likely to be involved in the pathogenesis of POAG. Treatment of TM cells with oxidative stress induced POAG-typical changes like ECM accumulation, cell death, disarrangement of the cytoskeleton, advanced senescence and the release of inflammatory markers. Oxidative stress is able to induce characteristic glaucomatous TM changes and these oxidative stress-induced TM changes can be minimized by the use of antioxidants, such as carnosine-related analogues and IOP-lowering substances. There is evidence demonstrating that carnosine related analogues may have antioxidative capacities, can prevent cellular senescence and the attrition of telomeres during the action of oxidative stress. Prevention of oxidative stress exposure to the TM with N-acetylcarnosine ophthalmic prodrug of carnosine and oral formulation of non-hydrolized carnosine may help to reduce the progression of POAG. The previous work has demonstrated that carnosine is able to reach the TM directly via the transcorneal and systemic pathways of administration with N-acetylcarnosine ophthalmic prodrug and oral formulation of non-hydrolized carnosine. We suggest in this article that dual therapy with N-acetylcarnosine lubricant eye drops, oral formulation of non-hydrolized carnosine combined with anti-glaucoma adrenergic drug may become the first-line therapy in glaucoma due to their efficiency in reducing IOP, prevention and reversal of oxidative stress-induced damages in TM and the low rate of severe side effects during combined treatment.     

Reactive oxygen species regulation of autophagy in cancer: Implications for cancer treatment

Reactive oxygen species (ROS) are important in regulating normal cellular processes, but deregulated ROS contribute to the development of various human diseases including cancers. Autophagy is one of the first lines of defense against oxidative stress damage. The autophagy pathway can be induced and upregulated in response to intracellular ROS or extracellular oxidative stress. This leads to selective lysosomal self-digestion of intracellular components to maintain cellular homeostasis. Hence, autophagy is the survival pathway, conferring stress adaptation and promoting viability under oxidative stress. However, increasing evidence has demonstrated that autophagy can also lead to cell death under oxidative stress conditions. In addition, altered autophagic signaling pathways that lead to decreased autophagy are frequently found in many human cancers. This review discusses the advances in understanding of the mechanisms of ROS-induced autophagy and how this process relates to tumorigenesis and cancer therapy.     

Proteasome inhibition by chronic oxidative stress in human trabecular meshwork cells

The pathophysiologic mechanisms leading to the malfunction of the trabecular meshwork (TM)-Schlemm's canal (SC) outflow pathway in glaucoma are still unclear. We hypothesize that chronic oxidative stress may contribute to the malfunction of the outflow pathway by impairing the intracellular proteasome system of the cells, decreasing the ability of the tissue to modulate outflow resistance. To study the effects of chronic oxidative stress on proteasome function, primary cultures of human TM cells were incubated under 40% oxygen and proteasome activity was analyzed by measuring the accumulation of enhanced green fluorescent protein fused to a PEST motif. Changes in proteasome content, cellular senescence, and cell viability were also monitored. After 10 days of exposure to chronic oxidative stress, TM cells showed a marked decline in proteasome activity that was associated with premature senescence and decreased cell viability. These results suggest that proteasome failure may be involved in glaucoma pathophysiology.     

Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells

Increasing evidence suggests oxidative damage as a key factor contributing to the failure of the conventional outflow pathway tissue to maintain appropriate levels of intraocular pressure, and thus increase the risk for developing glaucoma, a late-onset disease which is the second leading cause of permanent blindness worldwide. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors, including oxidative stress. Here, we have monitored, by using different methodologies (LC3-I to LC3-II turnover, tfLC3, and Cyto ID), the induction of autophagy and autophagy flux in TM cells subjected to a normobaric hyperoxic model of mild chronic oxidative stress. Our data indicate the MTOR-mediated activation of autophagy and nuclear translocation of TFEB in oxidatively stressed TM cells, as well as the role of autophagy in the occurrence of SA-GLB1/SA-β-gal. Concomitant with the activation of the autophagic pathway, TM cells grown under oxidative stress conditions displayed, however, reduced cathepsin (CTS) activities, reduced lysosomal acidification and impaired CTSB proteolytic maturation, resulting in decreased autophagic flux. We propose that diminished autophagic flux induced by oxidative stress might represent one of the factors leading to progressive failure of cellular TM function with age and contribute to the pathogenesis of primary open angle glaucoma.     

Cathepsin B Is Up-Regulated and Mediates Extracellular Matrix Degradation in Trabecular Meshwork Cells Following Phagocytic Challenge

Cells in the trabecular meshwork (TM), a tissue responsible for draining aqueous humor out of the eye, are known to be highly phagocytic. Phagocytic activity in TM cells is thought to play an important role in outflow pathway physiology. However, the molecular mechanisms triggered by phagocytosis in TM cells are unknown. Here we investigated the effects of chronic phagocytic stress on lysosomal function using different phagocytic ligands (E. coli, carboxylated beads, collagen I-coated beads, and pigment). Lysotracker red co-localization and electron micrographs showed the maturation of E. coli- and collagen I-coated beads-containing phagosomes into phagolysosomes. Maturation of phagosomes into phagolysosomes was not observed with carboxylated beads or pigment particles. In addition, phagocytosis of E. coli and collagen I-coated beads led to increased lysosomal mass, and the specific up-regulation and activity of cathepsin B (CTSB). Higher levels of membrane-bound and secreted CTSB were also detected. Moreover, in vivo zymography showed the intralysosomal degradation of ECM components associated with active CTSB, as well as an overall increased gelatinolytic activity in phagocytically challenged TM cells. This increased gelatinolytic activity with phagocytosis was partially blocked with an intracellular CTSB inhibitor. Altogether, these results suggest a potential role of phagocytosis in outflow pathway tissue homeostasis through the up-regulation and/or proteolytic activation of extracellular matrix remodeling genes.     

The octarepeat region of prion protein, but not the TM1 domain, is important for the antioxidant effect of prion protein

The cellular prion protein (PrP(c)) plays a crucial role in the pathogenesis of prion diseases, but its physiological function is far from understood. Several candidate functions have been proposed including binding and internalization of metal ions, a superoxide dismutase-like activity, regulation of cellular antioxidant activities, and signal transduction. The transmembrane (TM1) region of PrP(c) (residues 110-135) is particularly interesting because of its very high evolutionary conservation. We investigated a possible role of TM1 in the antioxidant defense, by assessing the impact of overexpressing wt-PrP or deletion mutants in N(2)A mouse neuroblastoma cells on intracellular reactive oxygen species (ROS) levels. Under conditions of oxidative stress, intracellular ROS levels were significantly lowered in cells overexpressing either wild-type PrP(c) (wt-PrP) or a deletion mutant affecting TM1 (Delta8TM1-PrP), but, as expected, not in cultures overexpressing a deletion mutant lacking the octapeptide region (Deltaocta-PrP). Overexpression of wt-PrP, Delta8TM1-PrP, or Deltaocta-PrP did not affect basal ROS levels. Interestingly, the mitochondrial membrane potential was significantly lowered in Deltaocta-PrP-transfected cultures in the absence of oxidative stress. We conclude that the protective effect of PrP(c) against oxidative stress involves the octarepeat region but not the TM1 domain nor the high-affinity copper binding site described for human residues His96/His111.     

Autophagy as a second level protective process in conferring resistance to environmentally-induced oxidative stress

This conceptual paper addresses the role of lysosomal autophagy in cellular defense against environmentally-induced oxidative stress using a marine mollusc (the blue mussel) as an experimental model. It is proposed that augmented autophagic removal of oxidatively damaged organelles and proteins provides a second level or tier of defense against oxidative stress. Age pigment or lipofuscin is a product of oxidative attack on proteins and lipids and can accumulate in lysosomes, where it may generate further reactive oxygen species (ROS) and inhibit lysosomal function, resulting in autophagic failure. The previously observed protective role of augmented autophagy, induced by nutritional deprivation, against oxidative stress can be explained by this model, where autophagy boosts "cellular housekeeping" through enhanced removal of ROS-damaged proteins and organelles minimizing formation of potentially harmful stress/age pigment, and has been proposed as an anti-aging mechanism. Finally, the probable low level triggering of autophagy in mussels by fluctuating environmental regimes is considered as a potential protective mechanism that will contribute to resistance to environmentally induced oxidative stress. It is further conjectured that organisms making up functional ecological assemblages (communities) in fluctuating environments, where upregulation of autophagy should provide a selective advantage, may be pre-selected to be tolerant of pollutant-induced oxidative stress.     

Altered intracellular redox status in Gaucher disease fibroblasts and impairment of adaptive response against oxidative stress

Gaucher disease (GD) is a lysosomal storage disorder, due to glucosylceramide (GlcCer) accumulation in several body tissues, which causes cellular failure by yet unidentified mechanisms. Several evidence indicates that GD pathogenesis is associated to an impairment in intracellular redox state. In fibroblast primary cultures, reactive oxygen species (ROS) levels and protein carbonyl content resulted significantly increased in GD patients compared to healthy donors, suggesting that GD cells, facing a condition of chronic oxidative stress, have evolved an adaptive response to survive. The ROS rise is probably due to NAD(P)H oxidase activity, being inhibited by the treatment with diphenylene iodonium chloride. Interestingly, GD cells are more sensitive to H(2)O(2) induced cell death, suggesting a dysregulation in the adaptive response to oxidative stress in which APE1/Ref-1 plays a central role. We found that the cytoplasmic amounts of APE1/Ref-1 protein were significantly higher in GD fibroblasts with respect to controls, and that GD cells failed to upregulate its expression upon H(2)O(2) treatment. Both ROS and APE1/Ref-1 increases are due to GlcCer accumulation, being prevented by treatment of GD fibroblasts with Cerezyme and induced in healthy fibroblasts treated with conduritol-beta-epoxide. These data, suggesting that GD cells display an impairment in the cellular redox state and in the adaptive cellular response to oxidative stress, may open new perspectives in the comprehension of GD pathogenesis.     

The role of protein quality control in mitochondrial protein homeostasis under oxidative stress

Mitochondria contribute significantly to the cellular production of ROS. The deleterious effects of increased ROS levels have been implicated in a wide variety of pathological reactions. Apart from a direct detoxification of ROS molecules, protein quality control mechanisms are thought to protect protein functions in the presence of elevated ROS levels. The reactivities of molecular chaperones and proteases remove damaged polypeptides, maintaining enzyme activities, thereby contributing to cellular survival both under normal and stress conditions. We characterized the impact of oxidative stress on mitochondrial protein homeostasis by performing a proteomic analysis of isolated yeast mitochondria, determining the changes in protein abundance after ROS treatments. We identified a set of mitochondrial proteins as substrates of ROS‐dependent proteolysis. Enzymes containing oxidation‐sensitive prosthetic groups like iron/sulfur clusters represented major targets of stress‐dependent degradation. We found that several proteins involved in ROS detoxification were also affected. We identified the ATP‐dependent protease Pim1/LON as a major factor in the degradation of ROS‐modified soluble polypeptides localized in the matrix compartment. As Pim1/LON expression was induced significantly under ROS treatment, we propose that this protease system performs a crucial protective function under oxidative stress conditions.     

The octarepeat region of prion protein,but not the TM1 domain,is important for the antioxidant effect of prion protein

The cellular prion protein (PrP^c) plays a crucial role in the pathogenesis of prion diseases, but its physiological function is far from understood. Several candidate functions have been proposed including binding and internalization of metal ions, a superoxide dismutase-like activity, regulation of cellular antioxidant activities, and signal transduction. The transmembrane (TM1) region of PrP^c (residues 110–135) is particularly interesting because of its very high evolutionary conservation. We investigated a possible role of TM1 in the antioxidant defense, by assessing the impact of overexpressing wt-PrP or deletion mutants in N₂A mouse neuroblastoma cells on intracellular reactive oxygen species (ROS) levels. Under conditions of oxidative stress, intracellular ROS levels were significantly lowered in cells overexpressing either wild-type PrP^c (wt-PrP) or a deletion mutant affecting TM1 (Δ8TM1-PrP), but, as expected, not in cultures overexpressing a deletion mutant lacking the octapeptide region (Δocta-PrP). Overexpression of wt-PrP, Δ8TM1-PrP, or Δocta-PrP did not affect basal ROS levels. Interestingly, the mitochondrial membrane potential was significantly lowered in Δocta-PrP-transfected cultures in the absence of oxidative stress. We conclude that the protective effect of PrP^c against oxidative stress involves the octarepeat region but not the TM1 domain nor the high-affinity copper binding site described for human residues His96/His111.     

Acute exposure to prion infection induces transient oxidative stress progressing to be cumulatively deleterious with chronic propagation in vitro

Neuronal loss is a pathological feature of prion diseases for which increased reactive oxygen species (ROS) and consequent oxidative stress is one proposed mechanism. The processes underlying ROS production in prion disease and the precise relationship to misfolding of the prion protein remain obscure. Using cell culture models of prion infection we found that cells demonstrate a rapid, prion protein (PrP) dependent, increase in intracellular ROS following exposure to infectious inoculum. ROS production correlated with internalisation and increased intracellular protease resistant PrP (PrP^Res). The ROS increase was predominantly lysosomal in origin but not sustained, with cells adapting within 48 hours. Overall ROS levels remained normal in the chronically prion infected cell population; however a subpopulation characterised by loss of membrane phosphatidylserine asymmetry exhibited highly peroxidised intracellular aggregates that localised with PrP and intense caspase activation. These apoptotic cells showed increased ROS closely correlating with increased PrP^Res. Our findings demonstrate that a PrP-dependent, transient, increase in intracellular ROS is characteristic of acute cellular prion infection, while chronic phases of prion infection in vitro are associated with a significant subpopulation manifesting apoptosis accompanying heightened oxidative stress and increased PrP^Res burden. Such observations strengthen the direct links between heightened ROS and ongoing prion propagation with eventual cellular demise.     

Autophagy as a second level protective process in conferring resistance to environmentally-induced oxidative stress

This conceptual paper addresses the role of lysosomal autophagy in cellular defense against environmentally-induced oxidative stress using a marine mollusc (the blue mussel) as an experimental model. It is proposed that augmented autophagic removal of oxidatively damaged organelles and proteins provides a second level or tier of defense against oxidative stress. Age pigment or lipofuscin is a product of oxidative attack on proteins and lipids and can accumulate in lysosomes, where it may generate further reactive oxygen species (ROS) and inhibit lysosomal function, resulting in autophagic failure. The previously observed protective role of augmented autophagy, induced by nutritional deprivation, against oxidative stress can be explained by this model, where autophagy boosts “cellular housekeeping” through enhanced removal of ROS-damaged proteins and organelles minimizing formation of potentially harmful stress/age pigment, and has been proposed as an anti-aging mechanism. Finally, the probable low level triggering of autophagy in mussels by fluctuating environmental regimes is considered as a potential protective mechanism that will contribute to resistance to environmentally induced oxidative stress. It is further conjectured that organisms making up functional ecological assemblages (communities) in fluctuating environments, where upregulation of autophagy should provide a selective advantage, may be pre-selected to be tolerant of pollutant-induced oxidative stress.

Addendum to: Moore MN, Viarengo A, Donkin P, Hawkins AJS. Autophagic and lysosomal reactions to stress in the hepatopancreas of blue mussels. Aquat Toxicol 2007; 84:80–91.     

Antioxidant action of <Emphasis Type="Italic">Andrographis paniculata</Emphasis> on lymphoma

Regulation of the balance between production of reactive oxygen species (ROS) by cellular processes and its removal by antioxidant defense system maintains normal physiological processes. Any condition leading to increased ROS results in oxidative stress which has been related with a number of diseases including cancer. Improvement in antioxidant defense system is required to overcome the damaging effects of oxidative stress. Therefore in the present study, effect of the aqueous extract of a medicinal plant Andrographis paniculata (AP) on antioxidant defense system in liver is investigated in lymphoma bearing AKR mice. Estimating catalase, superoxide dismutase and glutathione S transferase monitored the antioxidant action. Oral administration of the aqueous extract of A. paniculata in different doses causes a significant elevation of catalase, superoxide dismutase and glutathione S transferase activities. It reveals the antioxidant action of the aqueous extract of AP, which may play a role in the anticarcinogenic activity by reducing the oxidative stress. LDH activity is known to increase in various cancers due to hypoxic condition. Lactate dehydrogenase is used as tumor marker. We find a significant decrease in LDH activity on treatment with AP, which indicates a decrease in carcinogenic activity. A comparison with Doxorubicin (DOX), an anticancerous drug, indicates that the aqueous extract of AP is more effective than DOX with respect to its effect on catalase, superoxide dismutase, glutathione S transferase as well as on lactate dehydrogenase activities in liver of lymphoma bearing mice.     

Environmental light and endogenous antioxidants as the main determinants of non-cancer ocular diseases

The human eye is constantly exposed to sunlight and artificial lighting. Exogenous sources of reactive oxygen species (ROS) such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins contribute to oxidative damage in ocular tissues. Long-term exposure to these insults places the aging eye at considerable risk for pathological consequences of oxidative stress. Furthermore, in eye tissues, mitochondria are an important endogenous source of ROS. Over time, all ocular structures, from the tear film to the retina, undergo oxidative stress, and therefore, the antioxidant defenses of each tissue assume the role of a safeguard against degenerative ocular pathologies. The ocular surface and cornea protect the other ocular tissues and are significantly exposed to oxidative stress of environmental origin. Overwhelming of antioxidant defenses in these tissues clinically manifests as pathologies including pterygium, corneal dystrophies, and endothelial Fuch's dystrophy. The crystalline lens is highly susceptible to oxidative damage in aging because its cells and their intracellular proteins are not turned over or replaced, thus providing the basis for cataractogenesis. The trabecular meshwork, which is the anterior chamber tissue devoted to aqueous humor drainage, has a particular susceptibility to mitochondrial oxidative injury that affects its endothelium and leads to an intraocular pressure increase that marks the beginning of glaucoma. Photo-oxidative stress can cause acute or chronic retinal damage. The pathogenesis of age-related macular degeneration involves oxidative stress and death of the retinal pigment epithelium followed by death of the overlying photoreceptors. Accordingly, converging evidence indicates that mutagenic mechanisms of environmental and endogenous sources play a fundamental pathogenic role in degenerative eye diseases.     

Possible role of differentially expressing novel protein markers (ligatin and fibulin‐7) in human aqueous humor and trabecular meshwork tissue in glaucoma progression

The pathological mechanism underlying glaucoma has always been a complex aspect of this permanently blinding disease but proteomic studies have been helpful in elucidating it to a great extent in several studies. This study was designed to evaluate the expression and to get an idea about the function of two novel markers (ligatin and fibulin‐7) identified in human aqueous humor (hAH) in relation to glaucomatous progression. A significant increase in the protein content of glaucomatous hAH compared to that of non‐glaucomatous controls (NG‐Ctrls) was observed. Ligatin, fibulin‐7, and its proteolysis were revealed in hAH of primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG) and NG‐Ctrls. Quantification confirmed no significant difference in expression of ligatin, whereas fibulin‐7 was significantly (P < 0.05) low in hAH of PACG in comparison to NG‐Ctrls and POAG. Importantly the immunohistochemical assay for both indicated their possible involvement in the maintenance of the appropriate structure of TM in vivo. Since oxidative stress is a major contributor to glaucomatous pathogenesis, in vitro analysis of nuclear and cytoplasmic fractions indicated intracellular changes in localization and expression of ligatin upon oxidative insult of human trabecular meshwork (TM) cells. While no such changes were found for fibulin‐7 expression. This was also corroborated with the immunocytochemical assay. Though a study with a small sample size, this is the first report which confirms the presence of ligatin and fibulin‐7 in hAH, quantified their differential expression, and indicated the possibility of their involvement in the maintenance of the TM structure.     

Mitochondrial DNA damage is sensitive to exogenous H(2)O(2) but independent of cellular ROS production in prostate cancer cells

Intrinsic oxidative stress through enhanced production of reactive oxygen species (ROS) in prostate and other cancers may contribute to cancer progression due to its stimulating effect on cancer growth. In this study, we investigate differential responses to exogenous oxidative stimuli between aggressive prostate cancer and normal cell lines and explore potential mechanisms through interactions between cytotoxicity, cellular ROS production and oxidative DNA damage. The circular, multi-copy mitochondrial DNA (mtDNA) is used as a sensitive surrogate to oxidative DNA damage. We demonstrate that exogenous H(2)O(2) induces preferential cytotoxicity in aggressive prostate cancer than normal cells; a cascade production of cellular ROS, composed mainly of superoxide (O(2)(-)), is shown to be a critical determinant of H(2)O(2)-induced selective toxicity in cancer cells. In contrast, mtDNA damage and copy number depletion, as measured by a novel two-phase strategy of the supercoiling-sensitive qPCR method, are very sensitive to exogenous H(2)O(2) exposure in both cancer and normal cell lines. Moreover, we demonstrate for the first time that the sensitive mtDNA damage response to exogenous H(2)O(2) is independent of secondary cellular ROS production triggered by several ROS modulators regardless of cell phenotypes. These new findings suggest different mechanisms underpinning cytotoxicity and DNA damage induced by oxidative stress and a susceptible phenotype to oxidative injury associated with aggressive prostate cancer cells in vitro.     

Pro-fibrotic pathway activation in trabecular meshwork and lamina cribrosa is the main driving force of glaucoma

While primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, it still does not have a clear mechanism that can explain all clinical cases of the disease. Elevated IOP is associated with increased accumulation of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) that prevents normal outflow of aqueous humor (AH) and has damaging effects on the fine mesh-like lamina cribrosa (LC) through which the optic nerve fibers pass. Applying a pathway analysis algorithm, we discovered that an elevated level of TGFβ observed in glaucoma-affected tissues could lead to pro-fibrotic pathway activation in TM and in LC. In turn, activated pro-fibrotic pathways lead to ECM remodeling in TM and LC, making TM less efficient in AH drainage and making LC more susceptible to damage from elevated IOP via ECM transformation in LC. We propose pathway targets for potential therapeutic interventions to delay or avoid fibrosis initiation in TM and LC tissues.     

Mitochondrial dysfunction and oxidative stress: a contributing link to acquired epilepsy?

Mitochondrial dysfunction and oxidative stress contribute to several neurologic disorders and have recently been implicated in acquired epilepsies such as temporal lobe epilepsy (TLE). Acquired epilepsy is typically initiated by a brain injury followed by a "latent period" whereby molecular, biochemical and other cellular alterations occur in the brain leading to chronic epilepsy. Mitochondrial dysfunction and oxidative stress are emerging as factors that not only occur acutely as a result of precipitating injuries such as status epilepticus (SE), but may also contribute to epileptogenesis and chronic epilepsy. Mitochondria are the primary site of reactive oxygen species (ROS) making them uniquely vulnerable to oxidative damage that may affect neuronal excitability and seizure susceptibility. This mini-review provides an overview of evidence suggesting the role of mitochondrial dysfunction and oxidative stress as acute consequences of injuries that are known to incite chronic epilepsy and their involvement in the chronic stages of acquired epilepsy.