# Ceramide-mediated mitochondrial damage in diabetic retinopathy investigated by novel microfluidic O2 sensing and bio-mimetic electrochemistry

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $372,932

## Abstract

Despite recent success in treatment approaches, diabetic retinopathy (DR) remains a
leading cause of progressive vision loss and blindness. Conceptual and technical breakthroughs
to identify novel targets and strategies to cure this complication are paramount. We believe that
such a breakthrough is offered by recent evidence of mitochondrial dysfunction in diabetic
retinopathy in combination with the data from large clinical trials demonstrating a strong
association between lipid abnormalities and DR progression, and the discovery that ceramide
affects mitochondrial function.
 Mitochondria play cornerstone role in cellular metabolism and even slight modification of
mitochondrial function can lead to pathology. Indeed, mitochondrial damage precedes
histopathological abnormalities in DR.
 Recent studies demonstrate that there is an intricate connection between ceramide and
mitochondrial function. Mitochondria have been shown to contain many sphingolipids including
sphingomyelin and ceramide, as well as enzymes of sphingolipid pathway. Ceramide-induced
restriction of respiratory chain function at the level of complex III, as well as succinate
accumulation has been shown to be a causative factor in ischemia/reperfusion and stroke-
induced tissue damage.
 In addition to effects on respiratory enzymes, ceramides were shown to contribute to
mitochondrial outer membrane permeability either through S1P and hexadecenal production
and activation of BAX/BAK, or directly through the formation of protein-permeable ceramide
channels in mitochondrial outer membranes. These channels are shown to play a key role in
the induction of apoptosis through the release of cytochrome c into the cytoplasm. We have
previously demonstrated that activation of acid sphingomyelinase is an important early event in
the pathogenesis of diabetic retinopathy. In this proposal we will test the overall hypothesis
that increased levels of mitochondrial ceramide upon ASM activation leads to a)
cytochrome c release and apoptosis and b) restriction on mitochondrial respiratory chain
function in REC and RPE cells in diabetes. As traditional polarographic or fluorescence
quenching (Seahorse) methods are not conducive for studies on limited amounts of available
retinal tissue and cells, we are developing a novel microfluidic method for functional
mitochondrial studies. We will utilize this novel methodology to assess the role of ASM
activation and ceramide production in mitochondrial damage in diabetic retina.

## Key facts

- **NIH application ID:** 9904655
- **Project number:** 5R01EY028049-03
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Julia V Busik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,932
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904655

## Citation

> US National Institutes of Health, RePORTER application 9904655, Ceramide-mediated mitochondrial damage in diabetic retinopathy investigated by novel microfluidic O2 sensing and bio-mimetic electrochemistry (5R01EY028049-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9904655. Licensed CC0.

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