# Diabetic Retinopathy, Mitochondria Damage and Long Non-coding RNAs

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2022 · $346,500

## Abstract

ABSTRACT
Retinopathy is one of the most-feared complications of diabetes. In the pathogenesis of this blinding disease,
retinal mitochondria become dysfunctional, the electron transport chain (ETC) is compromised, superoxide
levels are elevated, and while complex III activity is inhibited, complex I remains unchanged. Mitochondria
have their own small DNA (mtDNA), which lacks protective histones, but is packaged into nucleoids that
provide some protection and assist in its biogenesis. Diabetes damages mtDNA, impairs its biogenesis, and
downregulates gene expression of mtDNA-encoded cytochrome B (CYTB of complex III). Gene expression is
also regulated by long noncoding RNAs (LncRNAs), the RNAs with >200 nucleotides and no open reading
frame for translation, but they can bind to DNA or RNA, or can act as scaffolds to promote the interaction of
proteins. Although majority of the LncRNAs are encoded by nuclear DNA, mtDNA also encodes three
LncRNAs, LncND5 and LncND6 for complex I and LncCytB for complex III. Preliminary data show that in
hyperglycemic milieu, while LncCytB is downregulated, LncND5 and LncND6 remain unchanged, and
nucleoids are decreased and mtDNA sensitivity to nuclease digestion is increased. Based on these, our central
hypothesis is that `LncCytB downregulation in diabetes impairs mtDNA nucleoids and attenuates cytochrome B
transcription, damaging the mtDNA and the electron transport chain system, and the damaged mitochondria
lead to the development of retinopathy'.
Aim 1 will investigate the role of LncCytB in nucleoid formation, and the hypothesis predicts that `decrease in
LncCytB in diabetes impairs nucleoids, damaging mtDNA integrity and reducing its copy numbers'. Aim 2 will
examine the role of LncCytB in the regulation of the ETC, and will test the hypothesis that `downregulation of
LncCytB decreases transcription of CYTB, which inhibits the complex III activity and compromises the ETC
system'. Aim 3 will investigate the mechanism by which hyperglycemia downregulates LnCytB, and will
examine the role of mitochondrial-targeted RNAse P protein 1 in regulation of LncCytB in the mitochondria.
The plan will employ in vitro (human retinal endothelial cells) and in vivo (retinal microvessels from rodents)
models of diabetic retinopathy, and will utilize fully optimized molecular biological approaches. Our overall goal
is to identify novel regulatory mechanisms involved in the pathogenesis of diabetic retinopathy, specifically at
the level of mtDNA-encoded LncRNA in mitochondrial homeostasis. The testable central hypothesis is
innovative, and has significant translational impact as successful completion of our studies will provide strong
background for LncCytB as a potential therapeutic target to prevent the development/ progression of this sight-
threatening disease.

## Key facts

- **NIH application ID:** 10463078
- **Project number:** 1R01EY033516-01A1
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** RENU A. KOWLURU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $346,500
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463078

## Citation

> US National Institutes of Health, RePORTER application 10463078, Diabetic Retinopathy, Mitochondria Damage and Long Non-coding RNAs (1R01EY033516-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10463078. Licensed CC0.

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