Skip to main content
SpringerLink
Log in
Book cover

Retinal Degenerative Diseases pp 165–183Cite as

Mitochondrial Decay and Impairment of Antioxidant Defenses in Aging RPE Cells

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 664))

Abstract

In the eye, the retinal pigment epithelium (RPE) is exposed to a highly oxidative environment, partly due to elevated oxygen partial pressure from the choriocapillaris and to digestion of polyunsaturated fatty acid laden photoreceptor outer segments. Here we examined the vulnerability of RPE cells to stress and changes in their mitochondria with increased chronological aging and showed that there is greater sensitivity of the cells to oxidative stress, alterations in their mitochondrial number, size, shape, matrix density, cristae architecture, and membrane integrity as a function of age. These features correlate with reduced cellular levels of ATP, ROS, and [Ca2+]c, lower Δψm, increased [Ca2+]m sequestration and decreased expression of mtHsp70, UCP2, and SOD3. Mitochondrial decay, bioenergetic deficiencies, and weakened antioxidant defenses in RPE cells occur as early as age 62. With increased severity, these conditions may significantly reduce RPE function in the retina and contribute to age related retinal anomalies.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Amer J, Goldfarb A, Fibach E (2003) Flow cytometric measurement of reactive oxygen species production by normal and thalassaemic red blood cells. Eur J Haematol 70:84–90

    Article  CAS  PubMed  Google Scholar 

  • Armstrong JS (2006) Mitochondrial membrane permeabilization: the sine qua non for cell death. Bioessays 28:253–260

    Article  CAS  PubMed  Google Scholar 

  • Barja G (2004) Free radicals and aging. Trends Neurosci 27:595–600

    Article  CAS  PubMed  Google Scholar 

  • Beal MF (1998) Mitochondrial dysfunction in neurodegenerative diseases. Biochim Biophys Acta 1366:211–223

    Article  CAS  PubMed  Google Scholar 

  • Beal MF (2007) Mitochondria and neurodegeneration. Novartis Found Symp 287:183–192 discussion 192–196

    Article  CAS  PubMed  Google Scholar 

  • Beatty S, Koh H, Phil M et al (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45:115–134

    Article  CAS  PubMed  Google Scholar 

  • Beckman KB, Ames BN (1998) Mitochondrial aging: open questions. Ann NY Acad Sci 854:118–127

    Article  CAS  PubMed  Google Scholar 

  • Bereiter-Hahn J, Vöth M (1994) Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech 27:198–219

    Article  CAS  PubMed  Google Scholar 

  • Bertoni-Freddari C, Balietti M, Giorgetti B et al (2008) Selective decline of the metabolic competence of oversized synaptic mitochondria in the old monkey cerebellum. Rejuvenation Res 11:387–391

    Article  CAS  PubMed  Google Scholar 

  • Bertoni-Freddari C, Fattoretti P, Casoli T (1993) Morphological plasticity of synaptic mitochondria during aging. Brain Res 628:193–200

    Article  CAS  PubMed  Google Scholar 

  • Bertoni-Freddari C, Fattoretti P, Casoli T et al (2001) Quantitative cytochemical mapping of mitochondrial enzymes in rat cerebella. Micron 32:405–410

    Article  CAS  PubMed  Google Scholar 

  • Bertoni-Freddari C, Fattoretti P, Giorgetti B et al (2005) Age-related decline in metabolic competence of small and medium-sized synaptic mitochondria. Naturwissenschaften 92:82–85

    Article  CAS  PubMed  Google Scholar 

  • Bertoni-Freddari C, Fattoretti P, Paoloni R et al (2003) Inverse correlation between mitochondrial size and metabolic competence: a quantitative cytochemical study of cytochrome oxidase activity. Naturwissenschaften 90:68–71

    CAS  PubMed  Google Scholar 

  • Chen JH, Hales CN, Ozanne SE (2007) DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res 35:7417–7428

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Stern D, Yan SD (2006) Mitochondrial dysfunction and Alzheimer’s disease. Curr Alzheimer Res 3:515–520

    Article  CAS  PubMed  Google Scholar 

  • Czarna M, Jarmuszkiewicz W (2006) Role of mitochondria in reactive oxygen species generation and removal; relevance to signaling and programmed cell death. Postepy Biochem 52:145–156

    CAS  PubMed  Google Scholar 

  • Dahlem YA, Wolf G, Siemen D et al (2006) Combined modulation of the mitochondrial ATP-dependent potassium channel and the permeability transition pore causes prolongation of the biphasic calcium dynamics. Cell Calcium 39:387–400

    Article  CAS  PubMed  Google Scholar 

  • D’Cruz PM, Yasumura D, Weir J et al (2000) Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 9:645–651

    Article  PubMed  Google Scholar 

  • Degli Esposti M (2002) Measuring mitochondrial reactive oxygen species. Methods 26:335–340

    Article  CAS  PubMed  Google Scholar 

  • Deng X, Yin F, Lu X et al (2006) The apoptotic effect of brucine from the seed of Strychnos nux-vomica on human hepatoma cells is mediated via Bcl-2 and Ca2+ involved mitochondrial pathway. Toxicol Sci 91:59–69

    Article  CAS  PubMed  Google Scholar 

  • Dorey CK, Wu G, Ebenstein D (1989) Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci 30:1691–1699

    CAS  PubMed  Google Scholar 

  • Duchen MR (1999) Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signaling and cell death. J Physiol 16:1–17

    Article  Google Scholar 

  • Dunaief JL, Dentchev T, Ying GS et al (2002) The role of apoptosis in age-related macular degeneration. Arch Ophthalmol 120:1435–1442

    PubMed  Google Scholar 

  • Eckert A, Hauptmann S, Scherping I et al (2008) Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice. Neurodegener Dis 5:157–159

    Article  CAS  PubMed  Google Scholar 

  • Feher J, Kovacs I, Artico M et al (2006) Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol Aging 27:983–993

    Article  CAS  PubMed  Google Scholar 

  • Finsterer J (2007) Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu (UUR) mutation. Acta Neurol Scand 116:1–14

    Article  CAS  PubMed  Google Scholar 

  • Gal A, Li Y, Thompson DA (2000) Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet 26:270–271

    Article  CAS  PubMed  Google Scholar 

  • Gavin PD, Prescott M, Luff SE et al (2004) Cross-linking ATP synthase complexes in vivo eliminates mitochondrial cristae. J Cell Sci 117:2333–2343

    Article  CAS  PubMed  Google Scholar 

  • Green WR, Enger C (1993) Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 100:1519–1535

    CAS  PubMed  Google Scholar 

  • Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629

    Article  CAS  PubMed  Google Scholar 

  • Green WR, McDonnell PJ, Yeo JH (1985) Pathologic features of senile macular degeneration. Ophthalmology 92:615–627

    CAS  PubMed  Google Scholar 

  • Hageman GS, Luthert PJ, Victor Chong NH et al (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age related macular degeneration. Prog Retin Eye Res 20:705–732

    Article  CAS  PubMed  Google Scholar 

  • Hauptmann S, Scherping I, Dröse S et al (2008) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging Feb 21 30(10):1574–1586

    Article  PubMed  Google Scholar 

  • 34. Hayakawa N, Yokoyama H, Kato H et al (2008) Age-related alterations of oxidative stress markers in campal CA1 sector. Exp Mol Pathol May 20

    Google Scholar 

  • He Y, Ge J, Tombran-Tink J (2008b) Mitochondrial defects and dysfunction in calcium regulation in glaucomatous trabecular meshwork cells. Invest Ophthalmol Vis Sci 49:4912–4922

    Article  PubMed  Google Scholar 

  • He Y, Tombran-Tink J, Ge J et al (2008a) Mitochondrial complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: protection by antioxidants. Invest Ophthalmol Vis Sci 49:1447–1458

    Article  PubMed  Google Scholar 

  • Inoue M, Sato EF, Nishikawa M (2003) Mitochondrial generation of reactive oxygen species and its role in aerobic life. Curr Med Chem 10:2495–2505

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa K, Takenaga K, Akimoto M et al (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320:661–664

    Article  CAS  PubMed  Google Scholar 

  • Jackson JG, Thayer SA (2006) Mitochondrial modulation of Ca2+-induced Ca2+-release in rat sensory neurons. J Neurophysiol 96:1093–1104

    Article  CAS  PubMed  Google Scholar 

  • Jezek P, Hlavatá L (2005) Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int J Biochem Cell Biol 37:2478–2503

    Article  CAS  PubMed  Google Scholar 

  • Jin GF, Hurst JS, Godley BF (2001) Rod outer segments mediate mitochondrial DNA damage and apoptosis in human retinal pigment epithelium. Curr Eye Res 23:11–19

    Article  CAS  PubMed  Google Scholar 

  • Jin M, Yaung J, Kannan R et al (2005) Hepatocyte growth factor protects RPE cells from apoptosis induced by glutathione depletion. Invest Ophthalmol Vis Sci 46:4311–4319

    Article  PubMed  Google Scholar 

  • Karbowski M, Kurono C, Wozniak M et al (1999) Free radical-induced megamitochondria formation and apoptosis. Free Radic Biol Med 26:396–409

    Article  CAS  PubMed  Google Scholar 

  • Kimura K, Tanaka N, Nakamura N et al (2007) Knockdown of mitochondrial heat shock protein 70 promotes progeria-like phenotypes in caenorhabditis elegans. J Biol Chem 282:5910–5918

    Article  CAS  PubMed  Google Scholar 

  • Kirkwood TB (2005) Understanding the odd science of aging. Cell 120:437–447

    Article  CAS  PubMed  Google Scholar 

  • Kmiec B, Woloszynska M, Janska H (2006) Heteroplasmy as a common state of mitochondrial genetic information in plants and animals. Curr Genet 50:149–159

    Article  CAS  PubMed  Google Scholar 

  • Knott AB, Perkins G, Schwarzenbacher R et al (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9:505–518

    Article  CAS  PubMed  Google Scholar 

  • Ko YH, Delannoy M, Hullihen J et al (2003) Mitochondrial ATP synthasome. Cristae-enriched membranes and a multiwell detergent screening assay yield dispersed single complexes containing the ATP synthase and carriers for Pi and ADP/ATP. J Biol Chem 278:12305–12309

    Article  CAS  PubMed  Google Scholar 

  • Koopman WJ, Verkaart S, Visch HJ et al (2007) Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology? Am J Physiol Cell Physiol 293:C22–C29

    Article  CAS  PubMed  Google Scholar 

  • Krieger C, Duchen MR (2002) Mitochondria, Ca2+ and neurodegenerative disease. Eur J Pharm. 447:177–188

    Article  CAS  Google Scholar 

  • Kwong JQ, Henning MS, Starkov AA et al (2007) The mitochondrial respiratory chain is a modulator of apoptosis. J Cell Biol 179:1163–1177

    Article  CAS  PubMed  Google Scholar 

  • Laguens R (1971) Morphometric study of myocardial mitochondria in the rat. J Cell Biol 48:673–676

    Article  CAS  PubMed  Google Scholar 

  • Lane N (2006) Mitochondrial disease: powerhouse of disease. Nature 440:600–602

    Article  CAS  PubMed  Google Scholar 

  • Liang FQ, Godley BF (2003) Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration. Exp Eye Res 76:397–403

    Article  CAS  PubMed  Google Scholar 

  • Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  CAS  PubMed  Google Scholar 

  • Mancuso C, Scapagini G, Currò D et al (2007) Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders. Front Biosci 12:1107–1123

    Article  CAS  PubMed  Google Scholar 

  • McKay BS, Burke JM (1994) Separation of phenotypically distinct subpopulations of cultured human retinal pigment epithelial cells. Exp Cell Res 213:85–92

    Article  CAS  PubMed  Google Scholar 

  • Melov S (2004) Modeling mitochondrial function in aging neurons. Trends Neurosci 27:601–606

    Article  CAS  PubMed  Google Scholar 

  • Mironov SL, Ivannikov MV, Johansson M (2005) [Ca2+]i signaling between mitochondria and endoplasmic reticulum in neurons is regulated by microtubules. From mitochondrial permeability transition pore to Ca2+-induced Ca2+ release. J Biol Chem 280:715–721

    CAS  PubMed  Google Scholar 

  • Nordgaard CL, Karunadharma PP, Feng X et al (2008) Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration. Invest Ophthalmol Vis Sci 49:2848–2855

    Article  PubMed  Google Scholar 

  • Pamplona R, Barja G, Portero-Otín M (2002) Membrane fatty acid unsaturation, protection against oxidative stress, and maximum life span: a homeoviscous-longevity adaptation? Ann N Y Acad Sci 959:475–490

    Article  CAS  PubMed  Google Scholar 

  • Passos JF, Saretzki G, von Zglinicki T (2007) DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res 35:7505–7513

    Article  CAS  PubMed  Google Scholar 

  • Pavlovic J, Floros J, Phelps DS et al (2008) Differentiation of xenografted human fetal lung parenchyma. Early Hum Dev 84:181–193

    Article  PubMed  Google Scholar 

  • Penfold PL, Madigan MC, Gillies MC et al (2001) Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res 20:385–414

    Article  CAS  PubMed  Google Scholar 

  • Pätsi J, Kervinen M, Finel M et al (2008) Leber hereditary optic neuropathy mutations in the ND6 subunit of mitochondrial complex I affect ubiquinone reduction kinetics in a bacterial model of the enzyme. Biochem J 409:129–137

    Article  PubMed  Google Scholar 

  • Reeve AK, Krishnan KJ, Turnbull DM (2008) Age related mitochondrial degenerative disorders in humans. Biotechnol J 3:750–756

    Article  CAS  PubMed  Google Scholar 

  • Sasaki T, Unno K, Tahara S et al (2008) Age-related increase of superoxide generation in the brains of mammals and birds. Aging Cell 7:459–469

    Article  CAS  PubMed  Google Scholar 

  • Sastre J, Pallardó FV, García de la Asunción J et al (2000) Mitochondria, oxidative stress and aging. Free Radic Res 32:189–198

    Google Scholar 

  • Schapira AH (1999) Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Parkinsonism Relat Disord 5:139–143

    Article  CAS  PubMed  Google Scholar 

  • Sohal RS, Mockett RJ, Orr WC (2002) Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic Biol Med 33:575–586

    Article  CAS  PubMed  Google Scholar 

  • Solmi R, Pallotti F, Rugolo M et al (1994) Lack of major mitochondrial bioenergetic changes in cultured skin fibroblasts from aged individuals. Biochem Mol Biol Int 33:477–484

    CAS  PubMed  Google Scholar 

  • Song DD, Shults CW, Sisk A et al (2004) Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. Exp Neurol 186:158–172

    Article  CAS  PubMed  Google Scholar 

  • Stuart JA, Brown MF (2006) Mitochondrial DNA maintenance and bioenergetics. Biochim Biophys Acta 1757:79–89

    Article  CAS  PubMed  Google Scholar 

  • Suter M, Remé C, Grimm C et al (2000) Age-related macular degeneration. The lipofusion component N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells. J Biol Chem 275:39625–39630

    Article  CAS  PubMed  Google Scholar 

  • Takuma K, Yao J, Huang J et al (2005) ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J 19:597–598

    CAS  PubMed  Google Scholar 

  • Toescu EC, Verkhratsky A, Landfield PW (2004) Ca2+ regulation and gene expression in normal brain aging. Trends Neurosci Oct 27(10):614–620

    Article  CAS  Google Scholar 

  • Valente EM, Abou-Sleiman PM, Caputo V et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160

    Article  CAS  PubMed  Google Scholar 

  • Viña J, Sastre J, Pallardó FV et al (2006) Role of mitochondrial oxidative stress to explain the different longevity between genders: protective effect of estrogens. Free Radic Res 40:1359–1365

    Article  PubMed  Google Scholar 

  • Wakabayashi T (2002) Megamitochondria formation - physiology and pathology. J Cell Mol Med 6:497–538

    Article  CAS  PubMed  Google Scholar 

  • Wang AL, Lukas TJ, Yuan M et al (2008) Increased mitochondrial DNA damage and down-regulation of DNA repair enzymes in aged rodent retinal pigment epithelium and choroid. Mol Vis 14:644–651

    PubMed  Google Scholar 

  • Weiter JJ (1987) Phototoxic changes in the retina. In: Miller, D (ed) Clinical light damage to the eye. Springer-Verlag, New York

    Google Scholar 

  • Wenzel P, Schuhmacher S, Kienhöfer J et al (2008) Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction. Cardiovasc Res July 22 80:280–289

    Article  CAS  PubMed  Google Scholar 

  • Winkler BS, Boulton ME, Gottsch JD et al (1999) Oxidative damage and age-related macular degeneration. Mol Vis 5:32

    CAS  PubMed  Google Scholar 

  • Young RW (1987) Pathophysiology of age-related macular degeneration. Surv Ophthalmol 31:291–306

    Article  CAS  PubMed  Google Scholar 

  • Zagon IS, Sassani JW, Myers RL et al (2007) Naltrexone accelerates healing without compromise of adhesion complexes in normal and diabetic corneal epithelium. Brain Res Bull 72:18–24

    Article  CAS  PubMed  Google Scholar 

  • Zareba M, Raciti MW, Henry MM (2006) Oxidative stress in ARPE-19 cultures: do melanosomes confer cytoprotection? Free Radic Biol Med 40:87–100

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Ben Franklin Foundation, PA, USA, the National Basic Research Program of China (No. 2007CB512200), and the National Natural Science Foundation of China (No.30672275, No.30400486), NEI Core Grant P30 EY01931 (PI, Janice M Burke), and by an unrestricted grant from Research to Prevent Blindness, Inc. to the Medical College of Wisconsin. The first author received support from the China Scholarship Council.

Author information

Authors and Affiliations

  1. Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA

    Yuan He & Joyce Tombran-Tink

Authors
  1. Yuan He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joyce Tombran-Tink
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joyce Tombran-Tink .

Editor information

Editors and Affiliations

  1. Health Science Center, University of Oklahoma, Stanton L. Young Blvd. 608, Oklahoma City, 73104, USA

    Robert E. Anderson

  2. Division of Ophthalmology, Cleveland Clinic Foundation, Euclid Ave. 9500, Cleveland, 44195, USA

    Joe G. Hollyfield

  3. School of Medicine, University of California, San Francisco, Kirkham St. 10, San Francisco, 94143, USA

    Matthew M. LaVail

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

He, Y., Tombran-Tink, J. (2010). Mitochondrial Decay and Impairment of Antioxidant Defenses in Aging RPE Cells. In: Anderson, R., Hollyfield, J., LaVail, M. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 664. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1399-9_20

Download citation

Publish with us

Policies and ethics

Search

Navigation