Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes
Mitochondrial damage in the cells comprising inner (retinal endothelial cells) and outer (retinal pigment epithelium (RPE)) blood–retinal barriers (BRB) is known to precede the initial BRB breakdown and further histopathological abnormalities in diabetic retinopathy (DR). We previously demonstrated...
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doaj-4c6efc89cdb8414285f8aebd844aec082020-11-25T03:08:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-05-01213830383010.3390/ijms21113830Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in DiabetesYan Levitsky0Sandra S. Hammer1Kiera P. Fisher2Chao Huang3Travan L. Gentles4David J. Pegouske5Caimin Xi6Todd A. Lydic7Julia V. Busik8Denis A. Proshlyakov9Department of Physiology, Michigan State University, East Lansing, MI 48824, USADepartment of Physiology, Michigan State University, East Lansing, MI 48824, USADepartment of Physiology, Michigan State University, East Lansing, MI 48824, USADepartment of Physiology, Michigan State University, East Lansing, MI 48824, USADepartment of Physiology, Michigan State University, East Lansing, MI 48824, USADepartment of Chemistry, Michigan State University, East Lansing, MI 48824, USADepartment of Chemistry, Michigan State University, East Lansing, MI 48824, USADepartment of Physiology, Michigan State University, East Lansing, MI 48824, USADepartment of Physiology, Michigan State University, East Lansing, MI 48824, USADepartment of Chemistry, Michigan State University, East Lansing, MI 48824, USAMitochondrial damage in the cells comprising inner (retinal endothelial cells) and outer (retinal pigment epithelium (RPE)) blood–retinal barriers (BRB) is known to precede the initial BRB breakdown and further histopathological abnormalities in diabetic retinopathy (DR). We previously demonstrated that activation of acid sphingomyelinase (ASM) is an important early event in the pathogenesis of DR, and recent studies have demonstrated that there is an intricate connection between ceramide and mitochondrial function. This study aimed to determine the role of ASM-dependent mitochondrial ceramide accumulation in diabetes-induced RPE cell damage. Mitochondria isolated from streptozotocin (STZ)-induced diabetic rat retinas (7 weeks duration) showed a 1.64 ± 0.29-fold increase in the ceramide-to-sphingomyelin ratio compared to controls. Conversely, the ceramide-to-sphingomyelin ratio was decreased in the mitochondria isolated from ASM-knockout mouse retinas compared to wild-type littermates, confirming the role of ASM in mitochondrial ceramide production. Cellular ceramide was elevated 2.67 ± 1.07-fold in RPE cells derived from diabetic donors compared to control donors, and these changes correlated with increased gene expression of <i>IL-1β</i>, <i>IL-6</i>, and <i>ASM</i>. Treatment of RPE cells derived from control donors with high glucose resulted in elevated <i>ASM</i>, vascular endothelial growth factor (<i>VEGF</i>), and intercellular adhesion molecule 1 (<i>ICAM-1</i>) mRNA. RPE from diabetic donors showed fragmented mitochondria and a 2.68 ± 0.66-fold decreased respiratory control ratio (RCR). Treatment of immortalized cell in vision research (ARPE-19) cells with high glucose resulted in a 25% ± 1.6% decrease in citrate synthase activity at 72 h. Inhibition of ASM with desipramine (15 μM, 1 h daily) abolished the decreases in metabolic functional parameters. Our results are consistent with diabetes-induced increase in mitochondrial ceramide through an ASM-dependent pathway leading to impaired mitochondrial function in the RPE cells of the retina.https://www.mdpi.com/1422-0067/21/11/3830diabetesretinopathyacid sphingomyelinasemitochondriaceramidesphingolipid |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yan Levitsky Sandra S. Hammer Kiera P. Fisher Chao Huang Travan L. Gentles David J. Pegouske Caimin Xi Todd A. Lydic Julia V. Busik Denis A. Proshlyakov |
spellingShingle |
Yan Levitsky Sandra S. Hammer Kiera P. Fisher Chao Huang Travan L. Gentles David J. Pegouske Caimin Xi Todd A. Lydic Julia V. Busik Denis A. Proshlyakov Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes International Journal of Molecular Sciences diabetes retinopathy acid sphingomyelinase mitochondria ceramide sphingolipid |
author_facet |
Yan Levitsky Sandra S. Hammer Kiera P. Fisher Chao Huang Travan L. Gentles David J. Pegouske Caimin Xi Todd A. Lydic Julia V. Busik Denis A. Proshlyakov |
author_sort |
Yan Levitsky |
title |
Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes |
title_short |
Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes |
title_full |
Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes |
title_fullStr |
Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes |
title_full_unstemmed |
Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes |
title_sort |
mitochondrial ceramide effects on the retinal pigment epithelium in diabetes |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-05-01 |
description |
Mitochondrial damage in the cells comprising inner (retinal endothelial cells) and outer (retinal pigment epithelium (RPE)) blood–retinal barriers (BRB) is known to precede the initial BRB breakdown and further histopathological abnormalities in diabetic retinopathy (DR). We previously demonstrated that activation of acid sphingomyelinase (ASM) is an important early event in the pathogenesis of DR, and recent studies have demonstrated that there is an intricate connection between ceramide and mitochondrial function. This study aimed to determine the role of ASM-dependent mitochondrial ceramide accumulation in diabetes-induced RPE cell damage. Mitochondria isolated from streptozotocin (STZ)-induced diabetic rat retinas (7 weeks duration) showed a 1.64 ± 0.29-fold increase in the ceramide-to-sphingomyelin ratio compared to controls. Conversely, the ceramide-to-sphingomyelin ratio was decreased in the mitochondria isolated from ASM-knockout mouse retinas compared to wild-type littermates, confirming the role of ASM in mitochondrial ceramide production. Cellular ceramide was elevated 2.67 ± 1.07-fold in RPE cells derived from diabetic donors compared to control donors, and these changes correlated with increased gene expression of <i>IL-1β</i>, <i>IL-6</i>, and <i>ASM</i>. Treatment of RPE cells derived from control donors with high glucose resulted in elevated <i>ASM</i>, vascular endothelial growth factor (<i>VEGF</i>), and intercellular adhesion molecule 1 (<i>ICAM-1</i>) mRNA. RPE from diabetic donors showed fragmented mitochondria and a 2.68 ± 0.66-fold decreased respiratory control ratio (RCR). Treatment of immortalized cell in vision research (ARPE-19) cells with high glucose resulted in a 25% ± 1.6% decrease in citrate synthase activity at 72 h. Inhibition of ASM with desipramine (15 μM, 1 h daily) abolished the decreases in metabolic functional parameters. Our results are consistent with diabetes-induced increase in mitochondrial ceramide through an ASM-dependent pathway leading to impaired mitochondrial function in the RPE cells of the retina. |
topic |
diabetes retinopathy acid sphingomyelinase mitochondria ceramide sphingolipid |
url |
https://www.mdpi.com/1422-0067/21/11/3830 |
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