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

Kantorow, Marc; Hawse, John R.; Cowell, T.L.; Benhamed, Sonia; Pizarro, Gresin O.; Reddy, Venkat N.; Hejtmancik, J. Fielding

doi:10.1073/pnas.0403532101

Cited by 164 publications

(144 citation statements)

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“…This result agrees with previous data showing that MsrA protects against cell death elicited by other oxidative insults [20][21][22][23]. Evidence suggests that aggresome formation (coupled with autophagy) is a protective mechanism initiated by the cell to eliminate misfolded proteins with a high propensity to form toxic aggregates [16,40].…”

Section: Discussionsupporting

confidence: 93%

“…MsrA is present throughout the brain, including the substantia nigra [19]. Cells with increased or decreased levels of MsrA are relatively resistant or vulnerable to oxidative insults, respectively [18,[20][21][22][23]. MsrA protects cells from oxidative stress not only by repairing proteins damaged by methionine oxidation, but also by engaging in a cycle of methionine oxidation and reduction that ultimately results in ROS scavenging [18,22].…”

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confidence: 99%

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Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults

Liu

Hindupur

Nguyen

et al. 2008

Free Radical Biology and Medicine

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Parkinson's disease (PD) is a neurologic disorder characterized by dopaminergic cell death in the substantia nigra. PD pathogenesis involves mitochondrial dysfunction, proteasome impairment, and α-synuclein aggregation, insults that may be especially toxic to oxidatively stressed cells including dopaminergic neurons. The enzyme methionine sulfoxide reductase A (MsrA) plays a critical role in the antioxidant response by repairing methionine-oxidized proteins and by participating in cycles of methionine oxidation and reduction that have the net effect of consuming reactive oxygen species. Here, we show that MsrA suppresses dopaminergic cell death and protein aggregation induced by the complex I inhibitor rotenone or mutant α-synuclein, but not by the proteasome inhibitor MG132. By comparing the effects of MsrA and the small-molecule antioxidants N-acetyl-cysteine and vitamin E, we provide evidence that MsrA protects against PD-related stresses primarily via methionine sulfoxide repair rather than by scavenging reactive oxygen species. We also demonstrate that MsrA efficiently reduces oxidized methionine residues in recombinant α-synuclein. These findings suggest that enhancing MsrA function may be a reasonable therapeutic strategy in PD. Keywords aggresome; dopamine; glutathione; heat shock protein; methionine sulfoxide reductase; neurodegeneration; oxidative stress; Parkinson's disease; proteasome; protofibril; rotenone; synuclein Parkinson's disease (PD) is a neurologic disorder that involves a selective loss of dopaminergic neurons from the substantia nigra [1,2]. The postmortem brains of PD patients are characterized by reduced activity of mitochondrial complex I, an enzyme of the mitochondrial electron transport chain [3,4]. In turn, this defect may cause a 'leakage' of electrons from mitochondria, leading to the accumulation of reactive oxygen species (ROS) that damage *Corresponding author. Address: Jean-Christophe Rochet, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, RHPH 410A, West Lafayette, Indiana, 47907-209147907- . Fax: 765-494-1414. E-mail: rochet@pharmacy.purdue.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2009 August 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript proteins, lipids, and nucleic acids [3,5]. The brains of PD patients also show evidence of impaired proteasomal function [6], a defect that results in increased oxidative stress and decreased elimination...

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults

Liu

Hindupur

Nguyen

et al. 2008

Free Radical Biology and Medicine

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“…Kantorow et al (2004) localized MsrA to all regions of the human lens and demonstrated that overexpression of MsrA in lens epithelial cells could protect against H 2 O 2 mediated oxidative stress. Silencing of the MsrA gene using siRNA increased sensitivity to H 2 O 2 mediated oxidative stress in lens cells, interestingly the decrease in MsrA levels lead to decreased viability even in the absence of oxidative stress.…”

Section: The Methionine Sulfoxide Reductase Repair Systemmentioning

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

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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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“…Double-stranded siRNAs specific for MsrA were obtained as previously described (Kantorow et al, 2004). HLE cells were transfected using the Transmessenger Transfection Reagent Kit (Qiagen, Valencia, CA).…”

Section: Short Interfering Rna (Sirna)-targeted Gene Silencingmentioning

confidence: 99%

“…Msr activity has been detected in the human lens (Spector et al, 1982) and both MsrA (Kantorow et al, 2004) and MsrB (Marchetti et al, 2005) are required for protection of lens cells against oxidative stress induced lethality. Of the many systems that can defend the lens against oxidative stress damage, many are localized to the mitochondria suggesting that protection or repair of mitochondrial components is important for lens maintenance.…”

Section: Introductionmentioning

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

Cited by 164 publications

References 53 publications

Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults

Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults

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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