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Mitochondrial fusion and maintenance of mitochondrial homeostasis in diabetic retinopathy.
- Source :
-
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2019 Jun 01; Vol. 1865 (6), pp. 1617-1626. Date of Electronic Publication: 2019 Mar 25. - Publication Year :
- 2019
-
Abstract
- Mitochondria are dynamic in structure, and undergo continuous fusion-fission to maintain their homeostasis. In diabetes, retinal mitochondria are swollen, their membrane is damaged and mitochondrial fusion protein, mitofusin 2 (Mfn2), is decreased. DNA methylation machinery is also activated and methylation status of genes implicated in mitochondrial damage and biogenesis is altered. This study aims to investigate the role of mitochondrial fusion in the development of diabetic retinopathy, and to illustrate the molecular mechanism responsible for Mfn2 suppression. Using human retinal endothelial cells, manipulated for Mfn2, we investigated the role of fusion in mitochondrial structural and functional damage in diabetes. The molecular mechanism of its suppression in diabetic milieu was determined by investigating Mfn2 promoter DNA methylation, and confirmed using molecular and pharmacological inhibitors of DNA methylation. Similar studies were performed in the retinal microvasculature (prepared by hypotonic shock method) of diabetic rats, and human donors with documented diabetic retinopathy. Overexpression of Mfn2 prevented glucose-induced increase in mitochondrial fragmentation, decrease in complex III activity and increase in membrane permeability, mtDNA damage and apoptosis. High glucose hypermethylated Mfn2 promoter and decreased transcription factor (SP1) binding, and Dnmt inhibition protected Mfn2 promoter from these changes. In streptozotocin-induced diabetic rats, intravitreal administration of Dnmt1-siRNA attenuated Mfn2 promoter hypermethylation and restored its expression. Human donors with diabetic retinopathy confirmed Mfn2 promoter DNA hypermethylation. Thus, regulating Mfn2 and its epigenetic modifications by molecular/pharmacological means will protect mitochondrial homeostasis in diabetes, and could attenuate the development of retinopathy in diabetic patients.<br /> (Copyright © 2019. Published by Elsevier B.V.)
- Subjects :
- Adult
Aged
Animals
Cell Line
DNA (Cytosine-5-)-Methyltransferase 1 antagonists & inhibitors
DNA (Cytosine-5-)-Methyltransferase 1 genetics
DNA (Cytosine-5-)-Methyltransferase 1 metabolism
DNA Methylation
Diabetes Mellitus, Experimental chemically induced
Diabetes Mellitus, Experimental metabolism
Diabetes Mellitus, Experimental pathology
Diabetes Mellitus, Type 2 metabolism
Diabetes Mellitus, Type 2 pathology
Diabetic Retinopathy metabolism
Diabetic Retinopathy pathology
Endothelial Cells metabolism
Endothelial Cells pathology
GTP Phosphohydrolases metabolism
Homeostasis genetics
Humans
Male
Middle Aged
Mitochondria metabolism
Mitochondria pathology
Mitochondrial Dynamics
Mitochondrial Proteins metabolism
Promoter Regions, Genetic
RNA, Small Interfering genetics
RNA, Small Interfering metabolism
Rats
Rats, Wistar
Retina metabolism
Retina pathology
Signal Transduction
Sp1 Transcription Factor genetics
Sp1 Transcription Factor metabolism
Streptozocin administration & dosage
Diabetes Mellitus, Experimental genetics
Diabetes Mellitus, Type 2 genetics
Diabetic Retinopathy genetics
Epigenesis, Genetic
GTP Phosphohydrolases genetics
Mitochondria genetics
Mitochondrial Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1879-260X
- Volume :
- 1865
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Publication Type :
- Academic Journal
- Accession number :
- 30922813
- Full Text :
- https://doi.org/10.1016/j.bbadis.2019.03.013