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Mitochondrial fragmentation and dysfunction in diabetic retinopathy

糖尿病视网膜病变中的线粒体碎片和功能障碍

基本信息

批准号：
10092161
负责人：
Sayon Roy
金额：
$ 43.17万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092161
关键词：
Affect Apoptosis Apoptotic Autophagocytosis BCL2 gene Blindness Blood Vessels Blood capillaries Cell Death Cells Complications of Diabetes Mellitus Connexin 43 Data Development Diabetes Mellitus Diabetic Retinopathy Down-Regulation Endothelial Cells Event Functional disorder Genes Glucose Goals Heterogeneity In Vitro Lesion Membrane Potentials Mitochondria Molecular Morphology Mus OPA1 gene Oxygen Consumption Pathogenesis Pathogenicity Pericytes Permeability Play Prevention Process Rattus Retina Role Structure Testing Up-Regulation aging population attenuation base clinically relevant cytochrome c diabetic diabetic rat extracellular fusion gene in vivo inhibition of autophagy insight mitochondrial dysfunction mitochondrial membrane new therapeutic target novel novel therapeutic intervention overexpression preservation prevent retinal apoptosis

项目摘要

The overall goal of this project is to test the hypothesis that high glucose (HG)-induced upregulation of mitochondrial fission genes and inhibition of mitochondrial fusion genes, concomitant with decreased autophagy and mitochondrial connexin 43 (mtCx43) downregulation, promotes mitochondrial fragmentation and dysfunction; amelioration of these events would protect mitochondrial function and thereby prevent retinal vascular cell loss in diabetic retinopathy (DR). The hypothesis is based on findings that mitochondrial fission/fusion, autophagy, and mtCx43 play critical roles in maintaining mitochondrial morphology and function. Our previous studies show HG induces mitochondrial fragmentation and breakdown of the mitochondrial networks resulting in increased mitochondrial membrane potential heterogeneity, decreased oxygen consumption, altered extracellular acidification, increased cytochrome c release, and ultimately apoptosis of retinal vascular cells. Furthermore, HG decreases autophagy and mtCx43 expression in these cells. Our preliminary data indicates that HG increases expression of fission genes, Fis1 and Drp1, and decreases expression of fusion genes, Opa1 and Mfn2, in retinal vascular cells. Additionally, HG reduces autophagy/mitophagy, a process that removes dysfunctional cellular components including mitochondrial fragments, and thereby contributes to accumulation of fragmented mitochondria. We also observed HG reduces mtCx43 expression, and that HG-induced mtCx43 channel inhibition alters mitochondrial morphology and cytochrome c release in rat retinal endothelial cells. Furthermore, mitochondrial fragmentation was noted in retinal vascular cells of diabetic rats, and new data indicate decreased number of acellular capillaries and pericyte ghosts in retinal capillaries of diabetic Drp1+/- mice and Opa1+/- mice suggesting attenuation of mitochondrial fragmentation could be beneficial. Based on the information and preliminary data, we propose three Specific Aims to determine 1) whether inhibition of HG-induced mitochondrial fragmentation prevents apoptosis in retinal endothelial cells and pericytes in vitro, as well as in retinas of diabetic rats; 2) whether HG-induced decreased autophagy promotes accumulation of mitochondrial fragments and retinal vascular cell loss; and 3) whether altered mtCx43 expression contributes to the development of retinal vascular lesions in experimental DR. The proposed project is expected to identify novel mechanism(s) underlying retinal vascular cell loss involving mitochondrial abnormalities, and thus, provide insight into potential strategies to prevent these abnormalities related to vascular cell death in DR.

本项目的总体目标是验证高糖（HG）诱导的假说