# Mitochondrial fragmentation and dysfunction in diabetic retinopathy

> **NIH NIH R01** · BOSTON MEDICAL CENTER · 2021 · $431,650

## Abstract

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.

## Key facts

- **NIH application ID:** 10092161
- **Project number:** 5R01EY027082-04
- **Recipient organization:** BOSTON MEDICAL CENTER
- **Principal Investigator:** Sayon Roy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $431,650
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092161

## Citation

> US National Institutes of Health, RePORTER application 10092161, Mitochondrial fragmentation and dysfunction in diabetic retinopathy (5R01EY027082-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10092161. Licensed CC0.

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