Skip to main content
SpringerLink
Log in

Formation of S-(carboxymethyl)-cysteine in rat liver mitochondrial proteins: effects of caloric and methionine restriction

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Maillard reaction contributes to the chemical modification and cross-linking of proteins. This process plays a significant role in the aging process and determination of animal longevity. Oxidative conditions promote the Maillard reaction. Mitochondria are the primary site of oxidants due to the reactive molecular species production. Mitochondrial proteome cysteine residues are targets of oxidative attack due to their specific chemistry and localization. Their chemical, non-enzymatic modification leads to dysfunctional proteins, which entail cellular senescence and organismal aging. Previous studies have consistently shown that caloric and methionine restrictions, nutritional interventions that increase longevity, decrease the rate of mitochondrial oxidant production and the physiological steady-state levels of markers of oxidative damage to macromolecules. In this scenario, we have detected S-(carboxymethyl)-cysteine (CMC) as a new irreversible chemical modification in mitochondrial proteins. CMC content in mitochondrial proteins significantly correlated with that of the lysine-derived analog N ε-(carboxymethyl)-lysine. The concentration of CMC is, however, one order of magnitude lower compared with CML likely due in part to the lower content of cysteine with respect to lysine of the mitochondrial proteome. CMC concentrations decreases in liver mitochondrial proteins of rats subjected to 8.5 and 25 % caloric restriction, as well as in 40 and 80 % methionine restriction. This is associated with a concomitant and significant increase in the protein content of sulfhydryl groups. Data presented here evidence that CMC, a marker of Cys-AGE formation, could be candidate as a biomarker of mitochondrial damage during aging.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Agarwal S, Sohal RS (1994) Aging and protein oxidative damage. Mech Ageing Dev 75:11–19

    Article  PubMed  CAS  Google Scholar 

  • Ahmed N, Thornalley PJ, Dawczynski J, Franke S, Strobel J, Stein G, Haik GM (2003) Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins. Invest Ophthalmol Vis Sci 44:5287–5292

    Article  PubMed  Google Scholar 

  • Alt N, Carson JA, Alderson NL, Wang Y, Nagai R, Henle T, Thorpe SR, Baynes JW (2004) Chemical modification of muscle protein in diabetes. Arch Biochem Biophys 425:200–206

    Article  PubMed  CAS  Google Scholar 

  • Ayala V, Naudí A, Sanz A, Caro P, Portero-Otin M, Barja G, Pamplona R (2007) Dietary protein restriction decreases oxidative protein damage, peroxidizability index, and mitochondrial complex I content in rat liver. J Gerontol A Biol Sci Med Sci 62:352–360

    Article  PubMed  Google Scholar 

  • Bota DA, Davies KJ (2001) Protein degradation in mitochondria: implications for oxidative stress, aging and disease: a novel etiological classification of mitochondrial proteolytic disorders. Mitochondrion 1:33–49

    Article  PubMed  CAS  Google Scholar 

  • Caro P, Gómez J, López-Torres M, Sánchez I, Naudí A, Jove M, Pamplona R, Barja G (2008) Forty percent and eighty percent methionine restriction decrease mitochondrial ROS generation and oxidative stress in rat liver. Biogerontology 9:183–196

    Article  PubMed  CAS  Google Scholar 

  • Dean RT, Fu S, Stocker R, Davies MJ (1997) Biochemistry and pathology of radical-mediated protein oxidation. Biochem J 324:1–18

    PubMed  CAS  Google Scholar 

  • Dröge W (2002) Aging-related changes in the thiol/disulfide redox state: implications for the use of thiol antioxidants. Exp Gerontol 37:1333–1345

    Article  PubMed  Google Scholar 

  • Fu MX, Requena JR, Jenkins AJ, Lyons TJ, Baynes JW, Thorpe SR (1996) The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. J Biol Chem 271:9982–9986

    Article  PubMed  CAS  Google Scholar 

  • Gómez J, Caro P, Naudí A, Portero-Otin M, Pamplona R, Barja G (2007) Effect of 8.5 and 25 % caloric restriction on mitochondrial free radical production and oxidative stress in rat liver. Biogerontology 8:555–566

    Article  PubMed  Google Scholar 

  • Hamada Y, Araki N, Koh N, Nakamura J, Horiuchi S, Hotta N (1996) Rapid formation of advanced glycation end products by intermediate metabolites of glycolytic pathway and polyol pathway. Biochem Biophys Res Commun 228:539–543

    Article  PubMed  CAS  Google Scholar 

  • Hulbert AJ, Pamplona R, Buffenstein R, Buttemer WA (2007) Life and death: metabolic rate, membrane composition, and life span of animals. Physiol Rev 87:1175–1213

    Article  PubMed  CAS  Google Scholar 

  • Hurd TR, Costa NJ, Dahm CC, Beer SM, Brown SE, Filipovska A, Murphy MP (2005) Glutathionylation of mitochondrial proteins. Antioxid Redox Signal 7:999–1010

    Article  PubMed  CAS  Google Scholar 

  • Jolly RD, Palmer DN, Dalefield RR (2002) The analytical approach to the nature of lipofuscin (age pigment). Arch Gerontol Geriatr 34:205–217

    Article  PubMed  CAS  Google Scholar 

  • Kemp M, Go YM, Jones DP (2008) Nonequilibrium thermodynamics of thiol/disulfide redox systems: a perspective on redox systems biology. Free Radic Biol Med 44:921–937

    Article  PubMed  CAS  Google Scholar 

  • López-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, Cascajo MV, Allard J, Ingram DK, Navas P, de Cabo R (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA 103:1768–1773

    Article  PubMed  Google Scholar 

  • Martínez A, Portero-Otin M, Pamplona R, Ferrer I (2010) Protein targets of oxidative damage in human neurodegenerative diseases with abnormal protein aggregates. Brain Pathol 20:281–297

    Article  PubMed  Google Scholar 

  • Miquel J, Ferrándiz ML, De Juan E, Sevila I, Martínez M (1995) N-acetylcysteine protects against age-related decline of oxidative phosphorylation in liver mitochondria. Eur J Pharmacol 292:333–335

    PubMed  CAS  Google Scholar 

  • Monnier VM (2003) Intervention against the Maillard reaction in vivo. Arch Biochem Biophys 419:1–15

    Article  PubMed  CAS  Google Scholar 

  • Moosmann B, Behl C (2008) Mitochondrially encoded cysteine predicts animal lifespan. Aging Cell 7:32–46

    Article  PubMed  CAS  Google Scholar 

  • Moskovitz J, Bar-Noy S, Williams WM, Requena J, Berlett BS, Stadtman ER (2001) Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals. Proc Natl Acad Sci USA 98:12920–12925

    Article  PubMed  CAS  Google Scholar 

  • Mostafa AA, Randell EW, Vasdev SC, Gill VD, Han Y, Gadag V, Raouf AA, El Said H (2007) Plasma protein advanced glycation end products, carboxymethyl cysteine, and carboxyethyl cysteine, are elevated and related to nephropathy in patients with diabetes. Mol Cell Biochem 302:35–42

    Article  PubMed  CAS  Google Scholar 

  • Nagai R, Brock JW, Blatnik M, Baatz JE, Bethard J, Walla MD, Thorpe SR, Baynes JW, Frizzell N (2007) Succination of protein thiols during adipocyte maturation: a biomarker of mitochondrial stress. J Biol Chem 282:34219–34228

    Article  PubMed  CAS  Google Scholar 

  • Negre-Salvayre A, Salvayre R, Augé N, Pamplona R, Portero-Otín M (2009) Hyperglycemia and glycation in diabetic complications. Antioxid Redox Signal 11:3071–3109

    Article  PubMed  CAS  Google Scholar 

  • Pamplona R (2008) Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochim Biophys Acta 1777:1249–1262

    Article  PubMed  CAS  Google Scholar 

  • Pamplona R, Barja G (2006) Mitochondrial oxidative stress, aging and caloric restriction: the protein and methionine connection. Biochim Biophys Acta 1757:496–508

    Article  PubMed  CAS  Google Scholar 

  • Pamplona R, Barja G (2007) Highly resistant macromolecular components and low rate of generation of endogenous damage: two key traits of longevity. Ageing Res Rev 6:189–210

    Article  PubMed  CAS  Google Scholar 

  • Pamplona R, Barja G (2011) An evolutionary comparative scan for longevity-related oxidative stress resistance mechanisms in homeotherms. Biogerontology. [Epub ahead of print]

  • Portero-Otín M, Pamplona R, Ruiz MC, Cabiscol E, Prat J, Bellmunt MJ (1999) Diabetes induces an impairment in the proteolytic activity against oxidized proteins and a heterogeneous effect in nonenzymatic protein modifications in the cytosol of rat liver and kidney. Diabetes 48:2215–2220

    Article  PubMed  Google Scholar 

  • Rabbani N, Thornalley PJ (2008) Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress. Biochem Soc Trans 36:1045–1050

    Article  PubMed  CAS  Google Scholar 

  • Rebrin I, Sohal RS (2004) Comparison of thiol redox state of mitochondria and homogenates of various tissues between two strains of mice with different longevities. Exp Gerontol 39:1513–1519

    Article  PubMed  CAS  Google Scholar 

  • Requena JR, Chao CC, Levine RL, Stadtman ER (2001) Glutamic and aminoadipic semialdehydes are the main carbonyl products of metal-catalyzed oxidation of proteins. Proc Natl Acad Sci USA 98:69–74

    Article  PubMed  CAS  Google Scholar 

  • Sanz A, Pamplona R, Barja G (2006) Is the mitochondrial free radical theory of aging intact? Antioxid Redox Signal 8:582–599

    Article  PubMed  CAS  Google Scholar 

  • Schindeldecker M, Stark M, Behl C, Moosmann B (2011) Differential cysteine depletion in respiratory chain complexes enables the distinction of longevity from aerobicity. Mech Ageing Dev 132:171–179

    Article  PubMed  CAS  Google Scholar 

  • Schlotterer A, Kukudov G, Bozorgmehr F, Hutter H, Du X, Oikonomou D, Ibrahim Y, Pfisterer F, Rabbani N, Thornalley P, Sayed A, Fleming T, Humpert P, Schwenger V, Zeier M, Hamann A, Stern D, Brownlee M, Bierhaus A, Nawroth P, Morcos M (2009) C. elegans as model for the study of high glucose-mediated life span reduction. Diabetes 58:2450–2456

    Article  PubMed  CAS  Google Scholar 

  • Sohal RS (2002) Role of oxidative stress and protein oxidation in the aging process. Free Radic Biol Med 33:37–44

    Article  PubMed  CAS  Google Scholar 

  • Stadtman ER (2004) Cyclic oxidation and reduction of methionine residues of proteins in antioxidant defense and cellular regulation. Arch Biochem Biophys 423:2–5

    Article  PubMed  CAS  Google Scholar 

  • Thornalley PJ, Battah S, Ahmed N, Karachalias N, Agalou S, Babaei-Jadidi R, Dawnay A (2003) Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry. Biochem J 375:581–592

    Article  PubMed  CAS  Google Scholar 

  • Thorpe SR, Baynes JW (2003) Maillard reaction products in tissue proteins: new products and new perspectives. Amino Acids 25:275–281

    Article  PubMed  CAS  Google Scholar 

  • Wang Y (2002) Modification of cysteine residues in proteins: identification and quantitation of sulfhydryl AGEs. M.S. Thesis, University of South Carolina, Columbia, SC

  • Zeng J, Davies MJ (2005) Evidence for the formation of adducts and S-(carboxymethyl)cysteine on reaction of alpha-dicarbonyl compounds with thiol groups on amino acids, peptides, and proteins. Chem Res Toxicol 18:1232–1241

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported in part by I + D grants from the Spanish Ministry of Science and Innovation (BFU2008-00335/BFI and BFU2011-23888), and BSCH-UCM (2009–2010) to G.B; grant from the Spanish Ministry of Health (PI11/01532) to M.P.O; and grants from the Spanish Ministry of Science and Innovation (BFU2009-11879/BFI), and the Generalitat of Catalunya (2009SGR00735) to R.P.P. Caro and J. Gómez received predoctoral fellowships from the Ministry of Education and Science. We thank David Argiles for excellent technical assistance. The authors are grateful to the anonymous reviewers for criticisms and suggestions, which improved the manuscript. No competing financial interests exist.

Author information

Authors and Affiliations

  1. Department of Experimental Medicine, Faculty of Medicine, University of Lleida-IRBLleida, Street Montserrat Roig-2, 25008, Lleida, Spain

    Alba Naudí, Mariona Jové, Daniel Cacabelos, Victoria Ayala, Rosanna Cabre, Manuel Portero-Otín & Reinald Pamplona

  2. Department of Animal Physiology-II, Complutense University, 28040, Madrid, Spain

    Pilar Caro, José Gomez & Gustavo Barja

Authors
  1. Alba Naudí
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariona Jové
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel Cacabelos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Victoria Ayala
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rosanna Cabre
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pilar Caro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. José Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuel Portero-Otín
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gustavo Barja
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Reinald Pamplona
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reinald Pamplona.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Naudí, A., Jové, M., Cacabelos, D. et al. Formation of S-(carboxymethyl)-cysteine in rat liver mitochondrial proteins: effects of caloric and methionine restriction. Amino Acids 44, 361–371 (2013). https://doi.org/10.1007/s00726-012-1339-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-012-1339-2

Keywords

Search

Navigation