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  1. Article: Analysis of mitochondrial dynamics and function in the retinal pigment epithelium by high-speed high-resolution live imaging.

    Tan, Li Xuan / Li, Jianlong / Germer, Colin J / Lakkaraju, Aparna

    Frontiers in cell and developmental biology

    2022  Volume 10, Page(s) 1044672

    Abstract: Mitochondrial dysfunction is strongly implicated in neurodegenerative diseases including age-related macular degeneration (AMD), which causes irreversible blindness in over 50 million older adults worldwide. A key site of insult in AMD is the retinal ... ...

    Abstract Mitochondrial dysfunction is strongly implicated in neurodegenerative diseases including age-related macular degeneration (AMD), which causes irreversible blindness in over 50 million older adults worldwide. A key site of insult in AMD is the retinal pigment epithelium (RPE), a monolayer of postmitotic polarized cells that performs essential functions for photoreceptor health and vision. Recent studies from our group and others have identified several features of mitochondrial dysfunction in AMD including mitochondrial fragmentation and bioenergetic defects. While these studies provide valuable insight at fixed points in time, high-resolution, high-speed live imaging is essential for following mitochondrial injury in real time and identifying disease mechanisms. Here, we demonstrate the advantages of live imaging to investigate RPE mitochondrial dynamics in cell-based and mouse models. We show that mitochondria in the RPE form extensive networks that are destroyed by fixation and discuss important live imaging considerations that can interfere with accurate evaluation of mitochondrial integrity such as RPE differentiation status and acquisition parameters. Our data demonstrate that RPE mitochondria show localized heterogeneities in membrane potential and ATP production that could reflect focal changes in metabolism and oxidative stress. Contacts between the mitochondria and organelles such as the ER and lysosomes mediate calcium flux and mitochondrial fission. Live imaging of mouse RPE flatmounts revealed a striking loss of mitochondrial integrity in albino mouse RPE compared to pigmented mice that could have significant functional consequences for cellular metabolism. Our studies lay a framework to guide experimental design and selection of model systems for evaluating mitochondrial health and function in the RPE.
    Language English
    Publishing date 2022-10-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2022.1044672
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Optineurin tunes outside-in signaling to regulate lysosome biogenesis and phagocytic clearance in the retina.

    Tan, Li Xuan / Germer, Colin J / Thamban, Thushara / La Cunza, Nilsa / Lakkaraju, Aparna

    Current biology : CB

    2023  Volume 33, Issue 18, Page(s) 3805–3820.e7

    Abstract: Balancing the competing demands of phagolysosomal degradation and autophagy is a significant challenge for phagocytic tissues. Yet how this plasticity is accomplished in health and disease is poorly understood. In the retina, circadian phagocytosis and ... ...

    Abstract Balancing the competing demands of phagolysosomal degradation and autophagy is a significant challenge for phagocytic tissues. Yet how this plasticity is accomplished in health and disease is poorly understood. In the retina, circadian phagocytosis and degradation of photoreceptor outer segments by the postmitotic retinal pigment epithelium (RPE) are essential for healthy vision. Disrupted autophagy due to mechanistic target of rapamycin (mTOR) overactivation in the RPE is associated with blinding macular degenerations; however, outer segment degradation is unaffected in these diseases, indicating that distinct mechanisms regulate these clearance mechanisms. Here, using advanced imaging and mouse models, we identify optineurin as a key regulator that tunes phagocytosis and lysosomal capacity to meet circadian demands and helps prioritize outer segment clearance by the RPE in macular degenerations. High-resolution live-cell imaging implicates optineurin in scissioning outer segment tips prior to engulfment, analogous to microglial trogocytosis of neuronal processes. Optineurin is essential for recruiting light chain 3 (LC3), which anchors outer segment phagosomes to microtubules and facilitates phagosome maturation and fusion with lysosomes. This dynamically activates transcription factor EB (TFEB) to induce lysosome biogenesis in an mTOR-independent, transient receptor potential-mucolipin 1 (TRPML1)-dependent manner. RNA-seq analyses show that expression of TFEB target genes temporally tracks with optineurin recruitment and that lysosomal and autophagy genes are controlled by distinct transcriptional programs in the RPE. The unconventional plasma membrane-to-nucleus signaling mediated by optineurin ensures outer segment degradation under conditions of impaired autophagy in macular degeneration models. Independent regulation of these critical clearance mechanisms would help safeguard the metabolic fitness of the RPE throughout the organismal lifespan.
    MeSH term(s) Mice ; Animals ; Lysosomes/metabolism ; Phagocytosis ; Retinal Pigment Epithelium/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Macular Degeneration/metabolism
    Chemical Substances TOR Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2023-08-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1071731-6
    ISSN 1879-0445 ; 0960-9822
    ISSN (online) 1879-0445
    ISSN 0960-9822
    DOI 10.1016/j.cub.2023.07.031
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3208: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
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  3. Article ; Online: Complement activation, lipid metabolism, and mitochondrial injury: Converging pathways in age-related macular degeneration.

    Tan, Li Xuan / Germer, Colin J / La Cunza, Nilsa / Lakkaraju, Aparna

    Redox biology

    2020  Volume 37, Page(s) 101781

    Abstract: The retinal pigment epithelium (RPE) is the primary site of injury in non-neovascular age-related macular degeneration or dry AMD. Polymorphisms in genes that regulate complement activation and cholesterol metabolism are strongly associated with AMD, but ...

    Abstract The retinal pigment epithelium (RPE) is the primary site of injury in non-neovascular age-related macular degeneration or dry AMD. Polymorphisms in genes that regulate complement activation and cholesterol metabolism are strongly associated with AMD, but the biology underlying disease-associated variants is not well understood. Here, we highlight recent studies that have used molecular, biochemical, and live-cell imaging methods to elucidate mechanisms by which aging-associated insults conspire with AMD genetic risk variants to tip the balance towards disease. We discuss how critical functions including lipid metabolism, autophagy, complement regulation, and mitochondrial dynamics are compromised in the RPE, and how a deeper understanding of these mechanisms has helped identify promising therapeutic targets to preserve RPE homeostasis in AMD.
    MeSH term(s) Complement Activation/genetics ; Humans ; Lipid Metabolism/genetics ; Macular Degeneration/genetics ; Macular Degeneration/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Retinal Pigment Epithelium/metabolism
    Language English
    Publishing date 2020-11-02
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2701011-9
    ISSN 2213-2317 ; 2213-2317
    ISSN (online) 2213-2317
    ISSN 2213-2317
    DOI 10.1016/j.redox.2020.101781
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration.

    La Cunza, Nilsa / Tan, Li Xuan / Thamban, Thushara / Germer, Colin J / Rathnasamy, Gurugirijha / Toops, Kimberly A / Lakkaraju, Aparna

    JCI insight

    2021  Volume 6, Issue 9

    Abstract: Age-related macular degeneration (AMD) damages the retinal pigment epithelium (RPE), the tissue that safeguards photoreceptor health, leading to irreversible vision loss. Polymorphisms in cholesterol and complement genes are implicated in AMD, yet ... ...

    Abstract Age-related macular degeneration (AMD) damages the retinal pigment epithelium (RPE), the tissue that safeguards photoreceptor health, leading to irreversible vision loss. Polymorphisms in cholesterol and complement genes are implicated in AMD, yet mechanisms linking risk variants to RPE injury remain unclear. We sought to determine how allelic variants in the apolipoprotein E cholesterol transporter modulate RPE homeostasis and function. Using live-cell imaging, we show that inefficient cholesterol transport by the AMD risk-associated ApoE2 increases RPE ceramide, leading to autophagic defects and complement-mediated mitochondrial damage. Mitochondrial injury drives redox state-sensitive cysteine-mediated phase separation of ApoE2, forming biomolecular condensates that could nucleate drusen. The protective ApoE4 isoform lacks these cysteines and is resistant to phase separation and condensate formation. In Abca-/- Stargardt macular degeneration mice, mitochondrial dysfunction induces liquid-liquid phase separation of p62/SQSTM1, a multifunctional protein that regulates autophagy. Drugs that decrease RPE cholesterol or ceramide prevent mitochondrial injury and phase separation in vitro and in vivo. In AMD donor RPE, mitochondrial fragmentation correlates with ApoE and p62 condensates. Our studies demonstrate that major AMD genetic and biological risk pathways converge upon RPE mitochondria, and identify mitochondrial stress-mediated protein phase separation as an important pathogenic mechanism and promising therapeutic target in AMD.
    MeSH term(s) Animals ; Apolipoprotein E2/genetics ; Apolipoprotein E4/genetics ; Autophagy/physiology ; Biomolecular Condensates/metabolism ; Biomolecular Condensates/pathology ; Ceramides/metabolism ; Cholesterol/metabolism ; Complement System Proteins/metabolism ; Intravital Microscopy ; Macular Degeneration/genetics ; Macular Degeneration/metabolism ; Macular Degeneration/pathology ; Mice ; Mice, Knockout ; Mitochondria/metabolism ; Mitochondria/pathology ; Oxidative Stress ; Retinal Pigment Epithelium/metabolism ; Retinal Pigment Epithelium/pathology ; Sequestosome-1 Protein/metabolism
    Chemical Substances Apolipoprotein E2 ; Apolipoprotein E4 ; Ceramides ; Sequestosome-1 Protein ; Sqstm1 protein, mouse ; Complement System Proteins (9007-36-7) ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2021-05-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.142254
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Procollagen C-proteinase enhancer 1 (PCPE-1) functions as an anti-angiogenic factor and enhances epithelial recovery in injured cornea.

    Massoudi, Dawiyat / Germer, Colin J / Glisch, Jeffrey M / Greenspan, Daniel S

    Cell and tissue research

    2017  Volume 370, Issue 3, Page(s) 461–476

    Abstract: Procollagen C-proteinase enhancer 1 (PCPE-1) has been characterized as a protein capable of enhancing the activity of bone morphogenetic protein 1/tolloid-like proteinases in the biosynthetic processing of C-propeptides from procollagens I-III. This ... ...

    Abstract Procollagen C-proteinase enhancer 1 (PCPE-1) has been characterized as a protein capable of enhancing the activity of bone morphogenetic protein 1/tolloid-like proteinases in the biosynthetic processing of C-propeptides from procollagens I-III. This processing step is thought necessary to the formation of collagen I-III monomers capable of forming fibrils. Thus, PCPE-1 is predicted to play an important role in scarring, as scar tissue is predominantly composed of fibrillar collagen. Corneal scarring is of great clinical importance, as it leads to loss of visual acuity and, in severe cases, blindness. Here, we investigate a possible role for PCPE-1 in corneal scarring. Although differences in corneal opacity associated with scarring following injury of Pcolce
    MeSH term(s) Animals ; Cells, Cultured ; Collagen/metabolism ; Cornea/metabolism ; Corneal Injuries/pathology ; Corneal Keratocytes/metabolism ; Extracellular Matrix Proteins/genetics ; Extracellular Matrix Proteins/metabolism ; Glycoproteins/genetics ; Glycoproteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neovascularization, Physiologic/physiology ; Wound Healing/physiology
    Chemical Substances Extracellular Matrix Proteins ; Glycoproteins ; Pcolce protein, mouse ; Collagen (9007-34-5)
    Language English
    Publishing date 2017
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 125067-x
    ISSN 1432-0878 ; 0302-766X
    ISSN (online) 1432-0878
    ISSN 0302-766X
    DOI 10.1007/s00441-017-2689-6
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    In stock of ZB MED Cologne/Königswinter

    Ub I Zs.94: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  6. Article: Procollagen C-proteinase enhancer 1 (PCPE-1) functions as an anti-angiogenic factor and enhances epithelial recovery in injured cornea

    Massoudi, Dawiyat / Germer, Colin J / Glisch, Jeffrey M / Greenspan, Daniel S

    Cell and tissue research. 2017 Dec., v. 370, no. 3

    2017  

    Abstract: Procollagen C-proteinase enhancer 1 (PCPE-1) has been characterized as a protein capable of enhancing the activity of bone morphogenetic protein 1/tolloid-like proteinases in the biosynthetic processing of C-propeptides from procollagens I–III. This ... ...

    Abstract Procollagen C-proteinase enhancer 1 (PCPE-1) has been characterized as a protein capable of enhancing the activity of bone morphogenetic protein 1/tolloid-like proteinases in the biosynthetic processing of C-propeptides from procollagens I–III. This processing step is thought necessary to the formation of collagen I–III monomers capable of forming fibrils. Thus, PCPE-1 is predicted to play an important role in scarring, as scar tissue is predominantly composed of fibrillar collagen. Corneal scarring is of great clinical importance, as it leads to loss of visual acuity and, in severe cases, blindness. Here, we investigate a possible role for PCPE-1 in corneal scarring. Although differences in corneal opacity associated with scarring following injury of Pcolce −/− and wild-type (WT) mice using full-thickness excision or alkali burn models of corneal injury were not grossly apparent, differences in procollagen I processing levels between Pcolce −/− and WT primary corneal keratocytes were consistent with a role for PCPE-1 in corneal collagen deposition. An unexpected finding was that neoangiogenesis, which follows alkali burn cornea injury, was strikingly increased in Pcolce −/− cornea, compared to WT. A series of aortic ring assays confirmed the anti-angiogenic effects of PCPE-1. Another unexpected finding was of abnormalities of epithelial basement membrane and of re-epithelialization following Pcolce −/− corneal injury. Thus, PCPE-1 appears to be of importance as an anti-angiogenic factor and in re-epithelialization following injury in cornea and perhaps in other tissues as well.
    Keywords angiogenesis ; basement membrane ; blindness ; bone morphogenetic proteins ; collagen ; cornea ; excision ; mice ; models ; opacity ; proteinases
    Language English
    Dates of publication 2017-12
    Size p. 461-476.
    Publishing place Springer Berlin Heidelberg
    Document type Article
    ZDB-ID 125067-x
    ISSN 1432-0878 ; 0302-766X
    ISSN (online) 1432-0878
    ISSN 0302-766X
    DOI 10.1007/s00441-017-2689-6
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

    Z 46/352: Show issues

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  7. Article ; Online: Aberrant early endosome biogenesis mediates complement activation in the retinal pigment epithelium in models of macular degeneration.

    Kaur, Gulpreet / Tan, Li Xuan / Rathnasamy, Gurugirijha / La Cunza, Nilsa / Germer, Colin J / Toops, Kimberly A / Fernandes, Marie / Blenkinsop, Timothy A / Lakkaraju, Aparna

    Proceedings of the National Academy of Sciences of the United States of America

    2018  Volume 115, Issue 36, Page(s) 9014–9019

    Abstract: Abnormally enlarged early endosomes (EEs) are pathological features of neurodegenerative diseases, yet insight into the mechanisms and consequences of EE expansion remains elusive. Here, we report swollen apical EEs in the retinal pigment epithelium (RPE) ...

    Abstract Abnormally enlarged early endosomes (EEs) are pathological features of neurodegenerative diseases, yet insight into the mechanisms and consequences of EE expansion remains elusive. Here, we report swollen apical EEs in the retinal pigment epithelium (RPE) of aged human donors and in the pigmented
    MeSH term(s) ATP-Binding Cassette Transporters/deficiency ; Aged ; Aged, 80 and over ; Animals ; Ceramides/genetics ; Ceramides/metabolism ; Complement C3a/genetics ; Complement C3a/metabolism ; Disease Models, Animal ; Endosomes/genetics ; Endosomes/metabolism ; Endosomes/pathology ; Female ; Humans ; Macular Degeneration/congenital ; Macular Degeneration/genetics ; Macular Degeneration/metabolism ; Macular Degeneration/pathology ; Male ; Mice ; Mice, Knockout ; Retinal Pigment Epithelium/metabolism ; Retinal Pigment Epithelium/pathology ; Swine ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism
    Chemical Substances ATP-Binding Cassette Transporters ; Abca4 protein, mouse ; Ceramides ; Complement C3a (80295-42-7) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1)
    Language English
    Publishing date 2018-08-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1805039115
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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