Protein maintenance in aging and replicative senescence: a role for the peptide methionine sulfoxide reductases

doi:10.1016/j.bbapap.2004.08.018

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

Volume 1703, Issue 2, 17 January 2005, Pages 261-266

https://doi.org/10.1016/j.bbapap.2004.08.018 Get rights and content

Abstract

Cellular aging is characterized by the build-up of oxidatively modified protein that results, at least in part, from impaired redox homeostasis associated with the aging process. Protein degradation and repair are critical for eliminating oxidized proteins from the cell. Oxidized protein degradation is mainly achieved by the proteasomal system and it is now well established that proteasomal function is generally impaired with age. Specific enzymatic systems have been identified which catalyze the regeneration of cysteine and methionine following oxidation within proteins. Protein-bound methionine sulfoxide diastereoisomers S and R are repaired by the combined action of the enzymes MsrA and MsrB that are subsequently regenerated by thioredoxin/thioredoxin reductase. Importantly, the peptide methionine sulfoxide reductase system has been implicated in increased longevity and resistance to oxidative stress in different cell types and model organisms. In a previous study, we reported that peptide methionine sulfoxide reductase activity as well as gene and protein expression of MsrA are decreased in various organs as a function of age. More recently, we have shown that gene expression of both MsrA and MsrB2 (Cbs-1) is decreased during replicative senescence of WI-38 fibroblasts, and this decline is associated with an alteration in catalytic activity and the accumulation of oxidized protein. In this review, we will address the importance of protein maintenance in the aging process as well as in replicative senescence, with a special focus on regulation of the peptide methionine sulfoxide reductase systems.

Introduction

Accumulation of oxidized proteins is a hallmark of cellular aging that raises the problem of the efficacy of intracellular protein maintenance systems responsible for the elimination of oxidatively modified proteins [1], [2], [3]. Indeed, the steady-state level of oxidized proteins depends on the balance between the rate of protein oxidative damage and the rate of oxidized protein elimination upon degradation and repair (Fig. 1). Oxidized proteins have been shown to be degraded in the cytosol and the nucleus by the proteasomal system [4], while in mitochondria, oxidized protein degradation is achieved, at least in part, by the Lon protease [5]. In addition to degradation, certain types of oxidative damage affecting sulfur-containing amino acids have been found to be reversible, hence leading to the possibility that some oxidized proteins could be repaired by specific enzymatic systems. The thioredoxin/thioredoxin reductase system has long been recognized to reverse such oxidation products of cysteines as disulfide bonds and cysteine sulfenic acids within proteins [6]. Moreover, sulfiredoxin was recently evidenced as reversing cysteine sulfinic acids, albeit within the peroxiredoxin enzyme [7], [8]. Methionine can be readily oxidized to its sulfoxide, creating a new asymmetric center and two diastereoisomers, denoted S and R. The S and R forms can be reduced by the peptide methionine sulfoxide reductases A (MsrA) and B (Msr B), respectively [9], [10]. Accumulation of oxidized proteins during aging was first attributed to an age-related decline in proteasomal function in the cytosol [3] and/or impaired activity of the mitochondrial Lon protease [5], [11]. Nevertheless, the interesting possibility that repair systems for oxidized protein such as the peptide methionine sulfoxide reductase system, might also play a role in the age-related decline in protein maintenance, has recently been investigated [12], [13]. The different protein maintenance systems will first be described, along with their fate during cellular aging. Then, the role and regulation of the peptide methionine sulfoxide reductase system during the aging process will be addressed since oxidized protein build-up and impaired redox homeostasis may result, at least in part, from an impaired peptide methionine sulfoxide reductase system associated with aging and cellular senescence.

Section snippets

Protein damage and maintenance at the cellular level

Proteins are targets for oxidative damage and other oxidation-derived processes such as the conjugation with lipid peroxidation products and the formation of advanced glycated endproducts also referred as to glycoxidation [1]. Reactive oxygen species that are produced upon normal metabolism in organelles such as mitochondria and peroxisomes have been implicated in protein damage. Moreover, extrinsic factors such as UV irradiation and toxins also participate in the production of intracellular

Role of peptide methionine sulfoxide reductase enzymes in aging and replicative senescence

It is now well documented that the peptide methionine sulfoxide reductase system is involved in aging and in the lifespan of Escherichia coli, yeast, Drosophila and mammals, although its molecular mechanisms remain to be elucidated [39], [40], [41], [42]. Studies from the Stadtman and Hoshi's laboratories [41], [42] using knock-out mice and transgenic Drosophila, respectively, addressed the role of MsrA in lifespan regulation related to the antioxidant properties of the enzyme. In transgenic

Conclusion

Decreased protein maintenance, i.e. degradation and repair, has been raised as an important factor in aging and the slowing down of protein turnover is believed to account, at least in part, for the age-related accumulation of damaged protein. Indeed, protein degradation by both the proteasomal system and the mitochondrial Lon protease has generally been reported to decline with age and during replicative senescence. The oxidized protein repair enzymes peptide methionine sulfoxide reductases

Acknowledgements

The research at our Laboratory is supported by funds from MENRT and a European 6th Framework Program Grant (FOOD-CT-2003-506850).

References (48)

B.S. Berlett et al.
Protein oxidation in aging, disease, and oxidative stress
J. Biol. Chem.
(1997)
V.S. Sharov et al.
Diastereoselective reduction of protein-bound methionine sulfoxide by methionine sulfoxide reductase
FEBS Lett.
(1999)
R. Grimaud et al.
Repair of oxidized proteins. Identification of a new methionine sulfoxide reductase
J. Biol. Chem.
(2001)
C.R. Picot et al.
The peptide methionine sulfoxide reductases, MsrA and MsrB (hCBS-1), are downregulated during replicative senescence of human WI-38 fibroblasts
FEBS Lett.
(2004)
K.J. Davies
Degradation of oxidized proteins by the 20S proteasome
Biochimie
(2001)
F. Shang et al.
Removal of oxidatively damaged proteins from lens cells by the ubiquitin–proteasome pathway
Exp. Eye Res.
(2001)
J.N. Keller et al.
Possible involvement of proteasome inhibition in aging: implications for oxidative stress
Mech. Ageing Dev.
(2000)
G. Carrard et al.
Impairment of proteasome structure and function in aging
Int. J. Biochem. Cell Biol.
(2002)
P.A. Szweda et al.
Proteolysis, free radicals, and aging
Free Radic. Biol. Med.
(2002)
N. Chondrogianni et al.
Central role of the proteasome in senescence and survival of human fibroblasts: induction of a senescence-like phenotype upon its inhibition and resistance to stress upon its activation
J. Biol. Chem.
(2003)

A.L. Bulteau et al.

Oxidative modification and inactivation of the proteasome during coronary occlusion/reperfusion

J. Biol. Chem.

(2001)

M. Demasi et al.

Glutathiolation of the proteasome is enhanced by proteolytic inhibitors

Arch. Biochem. Biophys.

(2001)

P.G. Sullivan et al.

Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover

J. Biol. Chem.

(2004)

D.A. Bota et al.

Modulation of Lon protease activity and aconitase turnover during aging and oxidative stress

FEBS Lett.

(2002)

S. Vougier et al.

Essential role of methionine residues in calmodulin binding to Bordetella pertussis adenylate cyclase, as probed by selective oxidation and repair by the peptide methionine sulfoxide reductases

J. Biol. Chem.

(2004)

J. Chen et al.

Acceleration of P/C-type inactivation in voltage-gated K(+) channels by methionine oxidation

Biophys. J.

(2000)

C.G. Cho et al.

Modulation of glutathione and thioredoxin systems by calorie restriction during the aging process

Exp. Gerontol.

(2003)

J. Campisi

From cells to organisms: can we learn about aging from cells in culture?

Exp. Gerontol.

(2001)

K.B. Beckman et al.

The free radical theory of aging matures

Physiol. Rev.

(1998)

B. Friguet et al.

Protein degradation by the proteasome and its implications in aging

Ann. N.Y. Acad. Sci.

(2000)

R. Shringarpure et al.

Protein oxidation and 20S proteasome-dependent proteolysis in mammalian cells

Cell. Mol. Life Sci.

(2001)

D.A. Bota et al.

Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism

Nat. Cell Biol.

(2002)

A. Holmgren

Antioxidant function of thioredoxin and glutaredoxin systems

Antioxid. Redox Signal.

(2000)

B. Biteau et al.

ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin

Nature

(2003)

Cited by (61)

Proteome oxidative carbonylation during oxidative stress-induced premature senescence of WI-38 human fibroblasts
2018, Mechanisms of Ageing and Development
Citation Excerpt :
Oxidatively modified proteins build-up that occurs during ageing and cellular senescence is believed to result, at least in part, from the increase of reactive oxygen species and other toxic compounds coming from both cellular metabolism and external factors. Experimental evidence has also indicated that failure of protein maintenance systems such as the proteasome, can also be a major contributor to the age-associated accumulation of damaged proteins (Chondrogianni et al., 2003; Petropoulos and Friguet, 2005; Baraibar and Friguet, 2012) that is believed to participate to the age-related decline in cellular function. Although the proteasome peptidase activities were transiently decreased after oxidative stress, they were almost restored in the senescent cells after one week up to four weeks recovery periods while a build-up of carbonylated proteins is still observed.
Accumulation of oxidatively damaged proteins is a hallmark of cellular and organismal ageing, and is also a phenotypic feature shared by both replicative senescence and stress-induced premature senescence of human fibroblasts. Moreover, proteins that are building up as oxidized (i.e. the “Oxi-proteome”) during ageing and age-related diseases represent a restricted set of cellular proteins, indicating that certain proteins are more prone to oxidative carbonylation and subsequent intracellular accumulation. The occurrence of specific carbonylated proteins upon oxidative stress induced premature senescence of WI-38 human fibroblasts and their follow-up identification have been addressed in this study. Indeed, it was expected that the identification of these proteins would give insights into the mechanisms by which oxidatively damaged proteins could affect cellular function. Among these proteins, some are belonging to the cytoskeleton while others are mainly involved in protein quality control and/or biosynthesis as well as in redox and energy metabolism, the impairment of which has been previously associated with cellular ageing. Interestingly, the majority of these carbonylated proteins were found to belong to functional interaction networks pointing to signalling pathways that have been implicated in the oxidative stress response and subsequent premature senescence.
Protein oxidation in aging and the removal of oxidized proteins
2013, Journal of Proteomics
Citation Excerpt :
Therefore, Msrs are also indirectly involved in scavenging of ROS [57]. Due to these functions it is proposed that alterations in both, the methionine sulfoxide reductases [58–60] as well as thioredoxin/thioredoxin reductase system [61] are perhaps related to aging. In the past it has been shown that MsrA concentrations decline in different rat tissues during aging [62].
Reactive oxygen species (ROS) are generated constantly within cells at low concentrations even under physiological conditions. During aging the levels of ROS can increase due to a limited capacity of antioxidant systems and repair mechanisms. Proteins are among the main targets for oxidants due to their high rate constants for several reactions with ROS and their abundance in biological systems. Protein damage has an important influence on cellular viability since most protein damage is non-repairable, and has deleterious consequences on protein structure and function. In addition, damaged and modified proteins can form cross-links and provide a basis for many senescence-associated alterations and may contribute to a range of human pathologies.
Two proteolytic systems are responsible to ensure the maintenance of cellular functions: the proteasomal (UPS) and the lysosomal system. Those degrading systems provide a last line of antioxidative protection, removing irreversible damaged proteins and recycling amino acids for the continuous protein synthesis. But during aging, both systems are affected and their proteolytic activity declines significantly.
Here we highlight the recent advantages in the understanding of protein oxidation and the fate of these damaged proteins during aging. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine.
Proteomic quantification and identification of carbonylated proteins upon oxidative stress and during cellular aging
2013, Journal of Proteomics
Increased protein carbonyl content is a hallmark of cellular and organismal aging. Protein damage leading to the formation of carbonyl groups derives from direct oxidation of several amino acid side chains but can also derive through protein adducts formation with lipid peroxidation products and dicarbonyl glycating compounds. All these modifications have been implicated during oxidative stress, aging and age-related diseases. However, in most cases, the proteins targeted by these deleterious modifications as well as their consequences have not yet been clearly identified. Indeed, this is essential to determine whether and how these modified proteins are impacting on cellular function, on the development of the senescent phenotype and the pathogenesis of age-related diseases. In this context, protein modifications occurring during aging and upon oxidative stress as well as main proteomic methods for detecting, quantifying and identifying oxidized proteins are described. Relevant proteomics studies aimed at monitoring the extent of protein carbonylation and identifying the targeted proteins in the context of aging and oxidative stress are also presented. Proteomics approaches, i.e. fluorescent based 2D-gel electrophoresis and mass spectrometry methods, represent powerful tools for monitoring at the proteome level the extent of protein oxidative and related modifications and for identifying the targeted proteins.
Accumulation of damaged macromolecules, including oxidatively damaged (carbonylated) proteins, is a hallmark of cellular and organismal aging. Since protein carbonyls are the most commonly used markers of protein oxidation, different methods have been developed for the detection and quantification of carbonylated proteins. The identification of these protein targets is of valuable interest in order to understand the mechanisms by which damaged proteins accumulate and potentially affect cellular functions during oxidative stress, cellular senescence and/or aging in vivo. The specificity of hydrazide derivatives to carbonyl groups and the presence of a wide range of functional groups coupled to the hydrazide, allowed the design of novel strategies for the detection and quantification of carbonylated proteins. Of note is the importance of fluorescent probes for monitoring carbonylated proteins. Proteomics approaches, i.e. fluorescent based 2D-gel electrophoresis and mass spectrometry methods, represent powerful tools for monitoring at the proteome level the extent of protein oxidative and related modifications and for identifying the targeted proteins. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine.
Oxidative proteome modifications target specific cellular pathways during oxidative stress, cellular senescence and aging
2013, Experimental Gerontology
Oxidatively modified proteins build-up with age results, at least in part, from the increase of reactive oxygen species and other toxic compounds originating from both cellular metabolism and external factors. Experimental evidence has also indicated that failure of protein maintenance is a major contributor to the age-associated accumulation of damaged proteins. We have previously shown that oxidized proteins as well as proteins modified by lipid peroxidation and glycoxidation adducts are accumulating in senescent human WI-38 fibroblasts and reported that proteins targeted by these modifications are mainly involved in protein maintenance, energy metabolism and cytoskeleton. Alterations in the proteome of human muscle adult stem cells upon oxidative stress have also been recently analyzed. The carbonylated proteins identified were also found to be involved in key cellular functions, such as carbohydrate metabolism, protein maintenance, cellular motility and protein homeostasis. More recently, we have built a database of proteins modified by carbonylation, glycation and lipid peroxidation products during aging and age-related diseases, such as neurodegenerative diseases. Common pathways evidenced by enzymes involved in intermediate metabolism were found targeted by these modifications, although different tissues have been examined. These results underscore the implication of potential deleterious effects of protein irreversible oxidative modifications in key cellular pathways during aging and in the pathogenesis of age-related diseases.
Methionine oxidation perturbs the structural core of the prion protein and suggests a generic misfolding pathway
2012, Journal of Biological Chemistry
Citation Excerpt :
It is well established that methionine oxidation is a general feature of aging (26, 74). Furthermore, the performance of the repair enzyme, methionine sulfoxide reductase (Msr) (75), is compromised at older age and is known to determine stress resistance and life span in mammals (76, 77). One might expect the methionine repair enzyme Msr to have a protective effect in prion diseases; however, MsrA knock-out mice show incubation times similar to controls when inoculated with scrapie (78).
Oxidative stress and misfolding of the prion protein (PrP^C) are fundamental to prion diseases. We have therefore probed the effect of oxidation on the structure and stability of PrP^C. Urea unfolding studies indicate that H₂O₂ oxidation reduces the thermodynamic stability of PrP^C by as much as 9 kJ/mol. ¹H-¹⁵N NMR studies indicate methionine oxidation perturbs key hydrophobic residues on one face of helix-C as follows: Met-205, Val-209, and Met-212 together with residues Val-160 and Tyr-156. These hydrophobic residues pack together and form the structured core of the protein, stabilizing its ternary structure. Copper-catalyzed oxidation of PrP^C causes a more significant alteration of the structure, generating a monomeric molten globule species that retains its native helical content. Further copper-catalyzed oxidation promotes extended β-strand structures that lack a cooperative fold. This transition from the helical molten globule to β-conformation has striking similarities to a misfolding intermediate generated at low pH. PrP may therefore share a generic misfolding pathway to amyloid fibers, irrespective of the conditions promoting misfolding. Our observations support the hypothesis that oxidation of PrP destabilizes the native fold of PrP^C, facilitating the transition to PrP^Sc. This study gives a structural and thermodynamic explanation for the high levels of oxidized methionine in scrapie isolates.
Mitochondrial gene expression in the human annulus: In vivo data from annulus cells and selectively harvested senescent annulus cells
2011, Spine Journal
Citation Excerpt :
The authors suggest that downregulation of Msr diminishes the ability of senescent cells to cope to oxidative stress, thereby augmenting the effectiveness of oxidative damage during cell senescence and aging [48]. The authors suggest that, as a result, there is an accumulation of oxidized protein and impaired cellular redox homeostasis [50]. Oxidative stress has previously been recognized as present in the aging/degenerating human disc based on increased accumulation of N′-(carboxymethyl)lysine, a product of oxidative modification of glycated proteins [51].
Mitochondrial dysfunction is recognized during cell senescence and apoptosis, two important components of human disc aging/degeneration. We hypothesize that mitochondrial dysfunction is present in the degenerating and senescent annulus cells. The objective of the present study was to analyze gene expression profiles related to mitochondrial function in vivo.
This study had two objectives in the analysis of gene expression patterns related to mitochondria in the human annulus: First, to assess human annulus cells in a genome-wide microarray analysis approach to evaluate mitochondrial gene expression in annulus tissue from degenerated compared with healthier discs. Second, to use laser capture microdissection (LCM) to selectively isolate senescent versus nonsenescent annulus cells to evaluate their mitochondrial gene expression patterns.
Following approval by our Human Subjects Institutional Review Board, annulus cells from 20 human lumbar discs were analyzed for gene groups related to mitochondrial function; a subset was also analyzed, which focused on senescent versus nonsenescent annulus cells in a study of annulus cells from 10 lumbar discs.
Human annulus tissue was used in molecular studies following institutional review board approval.
Gene expression levels identified with microarray analyses were statistically evaluated using GeneSifter Web-based software (VizX Labs, Seattle, WA, USA).
Human annulus specimens were assessed for gene expression related to mitochondrial function. Approaches used whole annulus tissue and senescent or nonsenescent annulus cells selectively harvested using LCM. Microarray data were analyzed using gene ontology searches and GeneSifter Web-based software.
Analysis of annulus cells compared mitochondrial gene expression patterns in annulus cells from more degenerated discs with patterns in annulus cells derived from healthier discs. Important findings included significant upregulation of p53 and several proapoptotic genes (including apoptosis-inducing factor, mitochondrion-associated 1, BCL2-like 11 [an apoptosis facilitator]; caspase 7 apoptosis-related cysteine peptidase; proteasome 26S subunit nonadenosine triphosphatase 10, programmed cell death 6, and reticulon 3). Methionine sulfoxide reductase (Msr), a repair enzyme that reduces methionine sulfoxide residues in proteins damaged by oxidation, was also significantly upregulated (2.02-fold increase). The gene “membrane-associated ring finger (C3HC4) 5” was significantly upregulated and relevant because it is believed to play a role in preventing cell senescence acting to regulate mitochondrial quality control. Nitric oxide synthase 3 (endothelial nitric oxide synthase [eNOS]) showed a 5.9-fold downregulation in more degenerated versus healthier annulus cells. In LCM-harvested senescent cells, Msr was significantly downregulated in senescent versus nonsenescent cells, a finding previously recognized in other types of senescent cells.
Novel data showed that significant gene expression patterns are present in the human annulus related to mitochondrial dysfunction; changes were identified in important genes involving apoptosis, eNOS and Msr expressions, and solute carrier genes. Because current research efforts are focusing on bioactive compounds for mitochondria, we suggest that future biologic cell-based therapies for annulus degeneration should also consider mitochondrial-focused therapies.

View all citing articles on Scopus

View full text

Protein maintenance in aging and replicative senescence: a role for the peptide methionine sulfoxide reductases

Abstract

Introduction

Section snippets

Protein damage and maintenance at the cellular level

Role of peptide methionine sulfoxide reductase enzymes in aging and replicative senescence

Conclusion

Acknowledgements

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

FEBS Lett.

Biochimie

Exp. Eye Res.

Mech. Ageing Dev.

Int. J. Biochem. Cell Biol.

Free Radic. Biol. Med.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Biophys. J.

Exp. Gerontol.

Exp. Gerontol.

The free radical theory of aging matures

Physiol. Rev.

Protein degradation by the proteasome and its implications in aging

Ann. N.Y. Acad. Sci.

Protein oxidation and 20S proteasome-dependent proteolysis in mammalian cells

Cell. Mol. Life Sci.

Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism

Nat. Cell Biol.

Antioxidant function of thioredoxin and glutaredoxin systems

Antioxid. Redox Signal.

ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin

Nature