Skip to main content
Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology 6/2016

22.04.2016 | Pathology

Mitochondrial elongation in the macular RPE of aging monkeys, evidence of metabolic stress

verfasst von: Peter Gouras, L. Ivert, M. Neuringer, T. Nagasaki

Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology | Ausgabe 6/2016

Einloggen, um Zugang zu erhalten

Abstract

Purpose

This study was conducted to determine whether mitochondria of the macular retinal pigment epithelium (RPE) change with age in rhesus monkeys (Macaca mulatta). Mitochondria are the main instigators of oxidative stress, which has often been considered to play a role in the pathogenesis of age-related macular degeneration (AMD). Any pathological changes in the mitochondria of aging macular RPE, the main target of AMD, would be a clue to the pathogenesis of this common retinal degeneration afflicting both monkey and man.

Methods

Transmission electron microscopy was used to identify mitochondria and to determine their appearance, their density per unit area of RPE cytoplasm and their length. The eyes of seven monkeys, 1, 2, 6.5, 23, 26, 27 and 35 years of age, were studied. Measurements were kept separate for the basal, middle and apical third of each cell. The basal third of the macular RPE had many more mitochondria than the middle third, and the apical third was almost devoid of mitochondria.

Results

Mitochondrial number decreased and length increased with age. The increase in length was associated with an unusual clustering of mitochondria into parallel arrays of elongated mitochondria, with their long axis orthogonal to the basal membrane of the cell, structures not described before in RPE.

Conclusions

Mitochondrial elongation is associated with metabolic and/or oxidative stress, which implies that age produces stress in macular RPE. The increased clustering of very elongated mitochondria suggests that pathological changes occur in mitochondrial organization with age. These changes support the hypothesis that age-related mitochondrial dysfunction plays a role in the pathogenesis of AMD.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Cai J, Nelson KC, Wu M, Sternberg P Jr, Jones DP (2000) Oxidative damage and protection of the RPE. Prog Retin Eye Res 19:205–221CrossRefPubMed Cai J, Nelson KC, Wu M, Sternberg P Jr, Jones DP (2000) Oxidative damage and protection of the RPE. Prog Retin Eye Res 19:205–221CrossRefPubMed
2.
Zurück zum Zitat Frank RN (1998) “Oxidative protector” enzymes in the macular retinal pigment epithelium of aging eyes and eyes with age-related macular degeneration. Trans Am Ophthalmol Soc 96:635–689PubMedPubMedCentral Frank RN (1998) “Oxidative protector” enzymes in the macular retinal pigment epithelium of aging eyes and eyes with age-related macular degeneration. Trans Am Ophthalmol Soc 96:635–689PubMedPubMedCentral
3.
Zurück zum Zitat Hollyfield JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, Ufret RL, Salomon RG, Perez VL (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 14:194–198CrossRefPubMedPubMedCentral Hollyfield JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, Ufret RL, Salomon RG, Perez VL (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 14:194–198CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Jarrett SG, Boulton ME (2012) Consequences of oxidative stress in age-related macular degeneration. Mol Asp Med 33:399–417CrossRef Jarrett SG, Boulton ME (2012) Consequences of oxidative stress in age-related macular degeneration. Mol Asp Med 33:399–417CrossRef
5.
Zurück zum Zitat Winkler BS, Boulton ME, Gottsch JD, Sternberg P (1999) Oxidative damage and age-related macular degeneration. Mol Vis 5:32PubMedPubMedCentral Winkler BS, Boulton ME, Gottsch JD, Sternberg P (1999) Oxidative damage and age-related macular degeneration. Mol Vis 5:32PubMedPubMedCentral
7.
Zurück zum Zitat Picard M, Shirihai OS, Gentil BJ, Burelle Y (2013) Mitochondrial morphology transitions and functions: implications for retrograde signaling? Am J Physiol Regul Integr Comp Physiol 304:R393–R406CrossRefPubMedPubMedCentral Picard M, Shirihai OS, Gentil BJ, Burelle Y (2013) Mitochondrial morphology transitions and functions: implications for retrograde signaling? Am J Physiol Regul Integr Comp Physiol 304:R393–R406CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Terman A, Kurz T, Navratil M, Arriaga EA, Brunk UT (2010) Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid Redox Signal 12:503–535CrossRefPubMedPubMedCentral Terman A, Kurz T, Navratil M, Arriaga EA, Brunk UT (2010) Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid Redox Signal 12:503–535CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Zhao C, Yasumura D, Li X, Matthes M, Lloyd M, Nielsen G, Ahern K, Snyder M, Bok D, Dunaief JL, LaVail MM, Vollrath D (2011) mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest 121:369–383CrossRefPubMedPubMedCentral Zhao C, Yasumura D, Li X, Matthes M, Lloyd M, Nielsen G, Ahern K, Snyder M, Bok D, Dunaief JL, LaVail MM, Vollrath D (2011) mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest 121:369–383CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Feeney-Burns L, Hilderbrand ES, Eldridge S (1984) Aging human RPE: morphometric analysis of macular, equatorial, and peripheral cells. Invest Ophthalmol Vis Sci 25:195–200PubMed Feeney-Burns L, Hilderbrand ES, Eldridge S (1984) Aging human RPE: morphometric analysis of macular, equatorial, and peripheral cells. Invest Ophthalmol Vis Sci 25:195–200PubMed
12.
Zurück zum Zitat Schmidt SY, Peisch RD (1986) Melanin concentration in normal human retinal pigment epithelium. Regional variation and age-related reduction. Invest Ophthalmol Vis Sci 27:1063–1067PubMed Schmidt SY, Peisch RD (1986) Melanin concentration in normal human retinal pigment epithelium. Regional variation and age-related reduction. Invest Ophthalmol Vis Sci 27:1063–1067PubMed
13.
Zurück zum Zitat Gouras P, Brown K, Ivert L, Neuringer M (2011) A novel melano-lysosome in the retinal epithelium of rhesus monkeys. Exp Eye Res 93:937–946CrossRefPubMed Gouras P, Brown K, Ivert L, Neuringer M (2011) A novel melano-lysosome in the retinal epithelium of rhesus monkeys. Exp Eye Res 93:937–946CrossRefPubMed
14.
Zurück zum Zitat Feher J, Kovacs I, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C (2006) Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol Aging 27:983–993CrossRefPubMed Feher J, Kovacs I, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C (2006) Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol Aging 27:983–993CrossRefPubMed
15.
Zurück zum Zitat Mai S, Klinkenberg M, Auburger G, Bereiter-Hahn J, Jendrach M (2010) Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1. J Cell Sci 123:917–926CrossRefPubMed Mai S, Klinkenberg M, Auburger G, Bereiter-Hahn J, Jendrach M (2010) Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1. J Cell Sci 123:917–926CrossRefPubMed
16.
Zurück zum Zitat Navratil M, Terman A, Arriaga EA (2008) Giant mitochondria do not fuse and exchange their contents with normal mitochondria. Exp Cell Res 314:164–172CrossRefPubMed Navratil M, Terman A, Arriaga EA (2008) Giant mitochondria do not fuse and exchange their contents with normal mitochondria. Exp Cell Res 314:164–172CrossRefPubMed
17.
Zurück zum Zitat Unterluggauer H, Hutter E, Voglauer R, Grillari J, Voth M, Bereiter-Hahn J, Jansen-Durr P, Jendrach M (2007) Identification of cultivation-independent markers of human endothelial cell senescence in vitro. Biogerontology 8:383–397CrossRefPubMed Unterluggauer H, Hutter E, Voglauer R, Grillari J, Voth M, Bereiter-Hahn J, Jansen-Durr P, Jendrach M (2007) Identification of cultivation-independent markers of human endothelial cell senescence in vitro. Biogerontology 8:383–397CrossRefPubMed
18.
Zurück zum Zitat Yoon YS, Yoon DS, Lim IK, Yoon SH, Chung HY, Rojo M, Malka F, Jou MJ, Martinou JC, Yoon G (2006) Formation of elongated giant mitochondria in DFO-induced cellular senescence: involvement of enhanced fusion process through modulation of Fis1. J Cell Physiol 209:468–480CrossRefPubMed Yoon YS, Yoon DS, Lim IK, Yoon SH, Chung HY, Rojo M, Malka F, Jou MJ, Martinou JC, Yoon G (2006) Formation of elongated giant mitochondria in DFO-induced cellular senescence: involvement of enhanced fusion process through modulation of Fis1. J Cell Physiol 209:468–480CrossRefPubMed
19.
Zurück zum Zitat Zottini M, Barizza E, Bastianelli F, Carimi F, Lo Schiavo F (2006) Growth and senescence of Medicago truncatula cultured cells are associated with characteristic mitochondrial morphology. New Phytol 172:239–247CrossRefPubMed Zottini M, Barizza E, Bastianelli F, Carimi F, Lo Schiavo F (2006) Growth and senescence of Medicago truncatula cultured cells are associated with characteristic mitochondrial morphology. New Phytol 172:239–247CrossRefPubMed
20.
Zurück zum Zitat Jahani-Asl A, Cheung EC, Neuspiel M, MacLaurin JG, Fortin A, Park DS, McBride HM, Slack RS (2007) Mitofusin 2 protects cerebellar granule neurons against injury-induced cell death. J Biol Chem 282:23788–23798CrossRefPubMed Jahani-Asl A, Cheung EC, Neuspiel M, MacLaurin JG, Fortin A, Park DS, McBride HM, Slack RS (2007) Mitofusin 2 protects cerebellar granule neurons against injury-induced cell death. J Biol Chem 282:23788–23798CrossRefPubMed
21.
Zurück zum Zitat Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15:5001–5011CrossRefPubMedPubMedCentral Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15:5001–5011CrossRefPubMedPubMedCentral
22.
Zurück zum Zitat Sugioka R, Shimizu S, Tsujimoto Y (2004) Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis. J Biol Chem 279:52726–52734CrossRefPubMed Sugioka R, Shimizu S, Tsujimoto Y (2004) Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis. J Biol Chem 279:52726–52734CrossRefPubMed
23.
Zurück zum Zitat Knott AB, Bossy-Wetzel E (2008) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Ann N Y Acad Sci 1147:283–292CrossRefPubMedPubMedCentral Knott AB, Bossy-Wetzel E (2008) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Ann N Y Acad Sci 1147:283–292CrossRefPubMedPubMedCentral
24.
Zurück zum Zitat Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598CrossRefPubMedPubMedCentral Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Wang DB, Uo T, Kinoshita C, Sopher BL, Lee RJ, Murphy SP, Kinoshita Y, Garden GA, Wang HG, Morrison RS (2014) Bax interacting factor-1 promotes survival and mitochondrial elongation in neurons. J Neurosci 34:2674–2683CrossRefPubMedPubMedCentral Wang DB, Uo T, Kinoshita C, Sopher BL, Lee RJ, Murphy SP, Kinoshita Y, Garden GA, Wang HG, Morrison RS (2014) Bax interacting factor-1 promotes survival and mitochondrial elongation in neurons. J Neurosci 34:2674–2683CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat Coleman R, Silbermann M, Gershon D, Reznick AZ (1987) Giant mitochondria in the myocardium of aging and endurance-trained mice. Gerontology 33:34–39CrossRefPubMed Coleman R, Silbermann M, Gershon D, Reznick AZ (1987) Giant mitochondria in the myocardium of aging and endurance-trained mice. Gerontology 33:34–39CrossRefPubMed
27.
Zurück zum Zitat Tandler B, Dunlap M, Hoppel CL, Hassan M (2002) Giant mitochondria in a cardiomyopathic heart. Ultrastruct Pathol 26:177–183CrossRefPubMed Tandler B, Dunlap M, Hoppel CL, Hassan M (2002) Giant mitochondria in a cardiomyopathic heart. Ultrastruct Pathol 26:177–183CrossRefPubMed
28.
Zurück zum Zitat Tandler B, Erlandson RA, Smith AL, Wynder EL (1969) Riboflavin and mouse hepatic cell structure and function. II. Division of mitochondria during recovery from simple deficiency. J Cell Biol 41:477–493CrossRefPubMedPubMedCentral Tandler B, Erlandson RA, Smith AL, Wynder EL (1969) Riboflavin and mouse hepatic cell structure and function. II. Division of mitochondria during recovery from simple deficiency. J Cell Biol 41:477–493CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Nordgaard CL, Karunadharma PP, Feng X, Olsen TW, Ferrington DA (2008) Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration. Invest Ophthalmol Vis Sci 49:2848–2855CrossRefPubMedPubMedCentral Nordgaard CL, Karunadharma PP, Feng X, Olsen TW, Ferrington DA (2008) Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration. Invest Ophthalmol Vis Sci 49:2848–2855CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Mitter SK, Song C, Qi X, Mao H, Rao H, Akin D, Lewin A, Grant M, Dunn W Jr, Ding J, Bowes Rickman C, Boulton M (2014) Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy 10:1989–2005CrossRefPubMedPubMedCentral Mitter SK, Song C, Qi X, Mao H, Rao H, Akin D, Lewin A, Grant M, Dunn W Jr, Ding J, Bowes Rickman C, Boulton M (2014) Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy 10:1989–2005CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Viiri J, Amadio M, Marchesi N, Hyttinen JM, Kivinen N, Sironen R, Rilla K, Akhtar S, Provenzani A, D’Agostino VG, Govoni S, Pascale A, Agostini H, Petrovski G, Salminen A, Kaarniranta K (2013) Autophagy activation clears ELAVL1/HuR-mediated accumulation of SQSTM1/p62 during proteasomal inhibition in human retinal pigment epithelial cells. PLoS One 8:e69563CrossRefPubMedPubMedCentral Viiri J, Amadio M, Marchesi N, Hyttinen JM, Kivinen N, Sironen R, Rilla K, Akhtar S, Provenzani A, D’Agostino VG, Govoni S, Pascale A, Agostini H, Petrovski G, Salminen A, Kaarniranta K (2013) Autophagy activation clears ELAVL1/HuR-mediated accumulation of SQSTM1/p62 during proteasomal inhibition in human retinal pigment epithelial cells. PLoS One 8:e69563CrossRefPubMedPubMedCentral
33.
Zurück zum Zitat Decanini A, Nordgaard CL, Feng X, Ferrington DA, Olsen TW (2007) Changes in select redox proteins of the retinal pigment epithelium in age-related macular degeneration. Am J Ophthalmol 143:607–615CrossRefPubMedPubMedCentral Decanini A, Nordgaard CL, Feng X, Ferrington DA, Olsen TW (2007) Changes in select redox proteins of the retinal pigment epithelium in age-related macular degeneration. Am J Ophthalmol 143:607–615CrossRefPubMedPubMedCentral
34.
Zurück zum Zitat Lin H, Xu H, Liang FQ, Liang H, Gupta P, Havey AN, Boulton ME, Godley BF (2011) Mitochondrial DNA damage and repair in RPE associated with aging and age-related macular degeneration. Invest Ophthalmol Vis Sci 52:3521–3529CrossRefPubMedPubMedCentral Lin H, Xu H, Liang FQ, Liang H, Gupta P, Havey AN, Boulton ME, Godley BF (2011) Mitochondrial DNA damage and repair in RPE associated with aging and age-related macular degeneration. Invest Ophthalmol Vis Sci 52:3521–3529CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat Terluk MR, Kapphahn RJ, Soukup LM, Gong H, Gallardo C, Montezuma SR, Ferrington DA (2015) Investigating mitochondria as a target for treating age-related macular degeneration. J Neurosci 35:7304–7311CrossRefPubMedPubMedCentral Terluk MR, Kapphahn RJ, Soukup LM, Gong H, Gallardo C, Montezuma SR, Ferrington DA (2015) Investigating mitochondria as a target for treating age-related macular degeneration. J Neurosci 35:7304–7311CrossRefPubMedPubMedCentral
36.
Zurück zum Zitat Feeney L (1978) Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies. Invest Ophthalmol Vis Sci 17:583–600PubMed Feeney L (1978) Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies. Invest Ophthalmol Vis Sci 17:583–600PubMed
37.
Zurück zum Zitat Hogan MJ, Alvarado JA, Weddell JE (1971) Histology of the human eye: an atlas and textbook. Saunders, Philadelphia Hogan MJ, Alvarado JA, Weddell JE (1971) Histology of the human eye: an atlas and textbook. Saunders, Philadelphia
38.
Zurück zum Zitat Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247CrossRefPubMed Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247CrossRefPubMed
Metadaten
Titel
Mitochondrial elongation in the macular RPE of aging monkeys, evidence of metabolic stress
verfasst von
Peter Gouras
L. Ivert
M. Neuringer
T. Nagasaki
Publikationsdatum
22.04.2016
Verlag
Springer Berlin Heidelberg
Erschienen in
Graefe's Archive for Clinical and Experimental Ophthalmology / Ausgabe 6/2016
Print ISSN: 0721-832X
Elektronische ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-016-3342-x

Weitere Artikel der Ausgabe 6/2016

Graefe's Archive for Clinical and Experimental Ophthalmology 6/2016 Zur Ausgabe

Neu im Fachgebiet Augenheilkunde

Ophthalmika in der Schwangerschaft

Die Verwendung von Ophthalmika in der Schwangerschaft und Stillzeit stellt immer eine Off-label-Anwendung dar. Ein Einsatz von Arzneimitteln muss daher besonders sorgfältig auf sein Risiko-Nutzen-Verhältnis bewertet werden. In der vorliegenden …

Operative Therapie und Keimnachweis bei endogener Endophthalmitis

Vitrektomie Originalie

Die endogene Endophthalmitis ist eine hämatogen fortgeleitete, bakterielle oder fungale Infektion, die über choroidale oder retinale Gefäße in den Augapfel eingeschwemmt wird [ 1 – 3 ]. Von dort infiltrieren die Keime in die Netzhaut, den …

Bakterielle endogene Endophthalmitis

Vitrektomie Leitthema

Eine endogene Endophthalmitis stellt einen ophthalmologischen Notfall dar, der umgehender Diagnostik und Therapie bedarf. Es sollte mit geeigneten Methoden, wie beispielsweise dem Freiburger Endophthalmitis-Set, ein Keimnachweis erfolgen. Bei der …

So erreichen Sie eine bestmögliche Wundheilung der Kornea

Die bestmögliche Wundheilung der Kornea, insbesondere ohne die Ausbildung von lichtstreuenden Narben, ist oberstes Gebot, um einer dauerhaften Schädigung der Hornhaut frühzeitig entgegenzuwirken und die Funktion des Auges zu erhalten.   

Update Augenheilkunde

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.