The Effect of Up- and Downregulation of MnSOD Enzyme on Oxidative Stress in Human Lens Epithelial Cells

Matsui, Hironori; Lin, Lishan; Ho, Ye-Shih; Reddy, Venkat N.

doi:10.1167/iovs.02-0830

Cited by 30 publications

(21 citation statements)

References 38 publications

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“…In addition, positive control cells created by using a non-MsrA-overexpressing virus exhibited responses to H 2 O 2 exposure that were nearly identical to those of uninfected control cells (data not shown). The concentrations of H 2 O 2 used in this study to induce cell death fall well within the range of concentrations used in many other studies examining H 2 O 2 -induced cell death in multiple cell types including HLE cells (51), human retinal pigmented epithelial cells (52), and human neuroblastoma cells (53).…”

Section: Discussionmentioning

confidence: 66%

“…Compellingly, methionine sulfoxide levels increase in cataract (7), and as much as 60% of membrane bound protein methionines are present in an oxidized form (8). Although it has been established that numerous important oxidative stress and other defense systems function in the lens including ␣-crystallin (9), manganese superoxide dismutase (MnSOD) (10), copper͞zinc superoxide dismutase (CuZnSOD) (11), reduced glutathione (12)(13)(14), glutathione reductase (15), glutathione S-transferase (16), thioltransferase (17), catalase (18), and others, most of these systems are protective; that is, they do not reverse oxidative stress damage, and none work directly on oxidized methionines. Oxidation of methionine residues is associated with the loss of numerous protein activities and effects a multitude of biological functions (19)(20)(21)(22)(23)(24).…”

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confidence: 99%

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Methionine sulfoxide reductase A is important for lens cell viability and resistance to oxidative stress

Kantorow

Hawse

Cowell

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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164

134

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Age-related cataract, an opacity of the eye lens, is the leading cause of visual impairment in the elderly, the etiology of which is related to oxidative stress damage. Oxidation of methionine to methionine sulfoxide is a major oxidative stress product that reaches levels as high as 60% in cataract while being essentially absent from clear lenses. Methionine oxidation results in loss of protein function that can be reversed through the action of methionine sulfoxide reductase A (MsrA), which is implicated in oxidative stress protection and is an essential regulator of longevity in species ranging from Escherichia coli to mice. To establish a role for MsrA in lens protection against oxidative stress, we have examined the levels and spatial expression patterns of MsrA in the human lens and have tested the ability of MsrA to protect lens cells directly against oxidative stress. In the present report, we establish that MsrA is present throughout the human lens, where it is likely to defend lens cells and their components against methionine oxidation. We demonstrate that overexpression of MsrA protects lens cells against oxidative stress damage, whereas silencing of the MsrA gene renders lens cells more sensitive to oxidative stress damage. We also provide evidence that MsrA is important for lens cell function in the absence of exogenous stress. Collectively, these data implicate MsrA as a key player in lens cell viability and resistance to oxidative stress, a major factor in the etiology of age-related cataract.

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

Methionine sulfoxide reductase A is important for lens cell viability and resistance to oxidative stress

Kantorow

Hawse

Cowell

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

164

134

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“…MnSOD (SOD 2) in the mitochondrial matrix converts O 2 -generated by the electron transport chain to hydrogen peroxide. Up and down-regulation of SOD 2 has been shown to be important for protection of lens epithelial cells against oxidative stress (Matsui et al, 2003). CuZnSOD (SOD 1) is present in the intermembrane space in some cells types, where it also converts O 2 -to H 2 O 2 permitting further diffusion into the cytosol (Ott et al, 2007).…”

Section: Mitochondrial Protective and Repair Systemsmentioning

confidence: 99%

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Brennan¹,

Kantorow²

2009

Experimental Eye Research

160

141

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Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself (Lin and Beal, 2006). In the anterior segment of the eye, oxidative stress has been linked to lens cataract (Truscott, 2005) and glaucoma (Tezel, 2006) while in the posterior segment of the eye oxidative stress has been associated with macular degeneration (Hollyfield et al., 2008). Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O 2 -) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (˙OH), hydrogen peroxide (H 2 O 2 ) and peroxynitrite (OONO -). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria (Hansford et al., 1997). Generation of superoxide at complex I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane (Kakkar and Singh 2007). While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Figure 1.0). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr)

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“…Transformed human lens epithelial (HLE) cells (SRA01/04) (Matsui et al, 2003) were grown and cultured in Dulbecco's modified Eagle's medium (Invitrogen, Gaithersburg, MD) supplemented with 15% fetal bovine serum (Invitrogen), gentamicin (50 units/ml; Invitrogen), penicillin-streptomycin antibiotic mix (50 units/ml, Invitrogen) and Fungizone (5 µl/ml, Invitrogen) at 36.5 °C in the presence of 5% CO 2 .…”

Section: Cell Culturementioning

confidence: 99%

Silencing of the methionine sulfoxide reductase A gene results in loss of mitochondrial membrane potential and increased ROS production in human lens cells

Marchetti

Lee

Cowell

et al. 2006

Experimental Eye Research

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Accumulation of methionine sulfoxide (Met(O)) is a significant feature of human cataract and previous studies have shown that methionine sulfoxide reductase A (MsrA), which acts to repair Met (O), can defend human lens cells against oxidative stress induced cell death. A key feature of oxidative stress is increased reactive oxygen species (ROS) in association with loss of mitochondrial function. Here, we sought to establish a potential role for MsrA in the accumulation of ROS in lens cells and the corresponding mitochondrial membrane potential in these cells. Targeted gene silencing was used to establish populations of lens cells expressing different levels of MsrA, and the mitochondrial membrane potential and ROS levels of these cell populations were monitored. Decreased MsrA levels were found to be associated with loss of cell viability, decreased mitochondrial membrane potential, and increased ROS levels in the absence of oxidative stress. These effects were augmented upon oxidative stress treatment. These results provide evidence that MsrA is a major determinant for accumulation of ROS in lens cells and that increased ROS levels in lens cells are associated with a corresponding decrease in mitochondrial membrane potential that is likely related to the requirement for MsrA in lens cell viability.

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The Effect of Up- and Downregulation of MnSOD Enzyme on Oxidative Stress in Human Lens Epithelial Cells

Abstract: These findings demonstrate the protective effect of MnSOD in antioxidant defense of cultured lens epithelial cells. This approach to modulating the enzyme level in cultured cells provides a new experimental model for study of the role of antioxidant enzymes in the lens.

Cited by 30 publications

References 38 publications

Methionine sulfoxide reductase A is important for lens cell viability and resistance to oxidative stress

Methionine sulfoxide reductase A is important for lens cell viability and resistance to oxidative stress

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Silencing of the methionine sulfoxide reductase A gene results in loss of mitochondrial membrane potential and increased ROS production in human lens cells

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