Lack of the antioxidant enzyme methionine sulfoxide reductase A in mice impairs RPE phagocytosis and causes photoreceptor cone dysfunction
Methionine sulfoxide reductase A (MsrA) is a widely expressed antioxidant enzyme that counteracts oxidative protein damage and contributes to protein regulation by reversing oxidation of protein methionine residues. In retinal pigment epithelial (RPE) cells in culture, MsrA overexpression increases...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-06-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231721000665 |
| _version_ | 1818451414624501760 |
|---|---|
| author | Francesca Mazzoni Ying Dun Jade A. Vargas Emeline F. Nandrot Silvia C. Finnemann |
| author_facet | Francesca Mazzoni Ying Dun Jade A. Vargas Emeline F. Nandrot Silvia C. Finnemann |
| author_sort | Francesca Mazzoni |
| collection | DOAJ |
| description | Methionine sulfoxide reductase A (MsrA) is a widely expressed antioxidant enzyme that counteracts oxidative protein damage and contributes to protein regulation by reversing oxidation of protein methionine residues. In retinal pigment epithelial (RPE) cells in culture, MsrA overexpression increases phagocytic capacity by supporting mitochondrial ATP production. Here, we show elevated retinal protein carbonylation indicative of oxidation, decreased RPE mitochondrial membrane potential, and attenuated RPE phagocytosis in msra−/− mice. Moreover, electroretinogram recordings reveal decreased light responses specifically of cone photoreceptors despite normal expression and localization of cone opsins. Impairment in msra−/− cone-driven responses is similar from 6 weeks to 13 months of age. These functional changes match dramatic decreases in lectin-labeled cone sheaths and reduction in cone arrestin in msra−/− mice. Strikingly, cone defects in light response and in lectin-labeled cone sheath are completely prevented by dark rearing. Together, our data show that msra−/− mice provide a novel small animal model of preventable cone-specific photoreceptor dysfunction that may have future utility in analysis of cone dystrophy disease mechanisms and testing therapeutic approaches aiming to alleviate cone defects. |
| first_indexed | 2024-12-14T21:06:49Z |
| format | Article |
| id | doaj.art-0efcf6d862c644fc828b83acea40accc |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-14T21:06:49Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-0efcf6d862c644fc828b83acea40accc2022-12-21T22:47:23ZengElsevierRedox Biology2213-23172021-06-0142101918Lack of the antioxidant enzyme methionine sulfoxide reductase A in mice impairs RPE phagocytosis and causes photoreceptor cone dysfunctionFrancesca Mazzoni0Ying Dun1Jade A. Vargas2Emeline F. Nandrot3Silvia C. Finnemann4Center for Cancer, Genetic Diseases and Gene Regulation, Department of Biological Sciences, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USACenter for Cancer, Genetic Diseases and Gene Regulation, Department of Biological Sciences, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USACenter for Cancer, Genetic Diseases and Gene Regulation, Department of Biological Sciences, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USASorbonne Université, INSERM, CNRS, Institut de La Vision, 17 Rue Moreau, F-75012, Paris, FranceCenter for Cancer, Genetic Diseases and Gene Regulation, Department of Biological Sciences, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA; Corresponding author. Department of Biological Sciences, Larkin Hall, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA.Methionine sulfoxide reductase A (MsrA) is a widely expressed antioxidant enzyme that counteracts oxidative protein damage and contributes to protein regulation by reversing oxidation of protein methionine residues. In retinal pigment epithelial (RPE) cells in culture, MsrA overexpression increases phagocytic capacity by supporting mitochondrial ATP production. Here, we show elevated retinal protein carbonylation indicative of oxidation, decreased RPE mitochondrial membrane potential, and attenuated RPE phagocytosis in msra−/− mice. Moreover, electroretinogram recordings reveal decreased light responses specifically of cone photoreceptors despite normal expression and localization of cone opsins. Impairment in msra−/− cone-driven responses is similar from 6 weeks to 13 months of age. These functional changes match dramatic decreases in lectin-labeled cone sheaths and reduction in cone arrestin in msra−/− mice. Strikingly, cone defects in light response and in lectin-labeled cone sheath are completely prevented by dark rearing. Together, our data show that msra−/− mice provide a novel small animal model of preventable cone-specific photoreceptor dysfunction that may have future utility in analysis of cone dystrophy disease mechanisms and testing therapeutic approaches aiming to alleviate cone defects.http://www.sciencedirect.com/science/article/pii/S2213231721000665MsrAOxidative stressPhagocytosisPhotoreceptorsRetinaRetinal pigment epithelium |
| spellingShingle | Francesca Mazzoni Ying Dun Jade A. Vargas Emeline F. Nandrot Silvia C. Finnemann Lack of the antioxidant enzyme methionine sulfoxide reductase A in mice impairs RPE phagocytosis and causes photoreceptor cone dysfunction Redox Biology MsrA Oxidative stress Phagocytosis Photoreceptors Retina Retinal pigment epithelium |
| title | Lack of the antioxidant enzyme methionine sulfoxide reductase A in mice impairs RPE phagocytosis and causes photoreceptor cone dysfunction |
| title_full | Lack of the antioxidant enzyme methionine sulfoxide reductase A in mice impairs RPE phagocytosis and causes photoreceptor cone dysfunction |
| title_fullStr | Lack of the antioxidant enzyme methionine sulfoxide reductase A in mice impairs RPE phagocytosis and causes photoreceptor cone dysfunction |
| title_full_unstemmed | Lack of the antioxidant enzyme methionine sulfoxide reductase A in mice impairs RPE phagocytosis and causes photoreceptor cone dysfunction |
| title_short | Lack of the antioxidant enzyme methionine sulfoxide reductase A in mice impairs RPE phagocytosis and causes photoreceptor cone dysfunction |
| title_sort | lack of the antioxidant enzyme methionine sulfoxide reductase a in mice impairs rpe phagocytosis and causes photoreceptor cone dysfunction |
| topic | MsrA Oxidative stress Phagocytosis Photoreceptors Retina Retinal pigment epithelium |
| url | http://www.sciencedirect.com/science/article/pii/S2213231721000665 |
| work_keys_str_mv | AT francescamazzoni lackoftheantioxidantenzymemethioninesulfoxidereductaseainmiceimpairsrpephagocytosisandcausesphotoreceptorconedysfunction AT yingdun lackoftheantioxidantenzymemethioninesulfoxidereductaseainmiceimpairsrpephagocytosisandcausesphotoreceptorconedysfunction AT jadeavargas lackoftheantioxidantenzymemethioninesulfoxidereductaseainmiceimpairsrpephagocytosisandcausesphotoreceptorconedysfunction AT emelinefnandrot lackoftheantioxidantenzymemethioninesulfoxidereductaseainmiceimpairsrpephagocytosisandcausesphotoreceptorconedysfunction AT silviacfinnemann lackoftheantioxidantenzymemethioninesulfoxidereductaseainmiceimpairsrpephagocytosisandcausesphotoreceptorconedysfunction |