# Mitochondria-mediated mechanisms of ferroptosis in response to cardiac ischemia-reperfusion injury

> **NIH NIH R16** · UNIVERSITY OF PUERTO RICO MED SCIENCES · 2022 · $150,000

## Abstract

ABSTRACT
Coronary heart disease is the leading cause of mortality and morbidity worldwide that occurs due to the
detrimental effects of myocardial infarction (MI)/ischemia-reperfusion injury (IRI). Mechanisms of MI/IRI
are not completely clear, and hence, there are no effective therapeutic strategies; current therapeutic
approaches to mitigate heart damage mostly focus on restoring coronary perfusion but not limiting
reperfusion injury. Multiple forms of cell death occur at different stages of post-MI/IRI depending on the
severity of the disease. This project will elucidate the regulatory mechanisms of a recently discovered iron-
dependent programmed cell death, ferroptosis, in cardiac IRI. Ferroptosis arises via excessive oxygenation
of phospholipids (PLs) accompanied by the insufficient capacity of a selenoprotein glutathione peroxidase
4 (GPX4) to eliminate oxidized PLs, particularly, phosphatidylethanolamine (PEox) at the expense of
reduced glutathione (GSH). We have recently identified and quantified pro-ferroptotic PEox species in
response to RSL3 (GPX4 inhibitor, ferroptosis inducer) in cardiomyocytes by a state-of-art technique. In
addition, our preliminary studies revealed accumulation of ferroptotic PEox species in mitochondria
isolated from hearts exposed to global IRI as well as from cardiomyocytes challenged with RSL3. We
propose that mitochondria participate in MI/IRI-induced ferroptotic signaling through two major GSH-
dependent mechanisms: i) IR-induced mitochondrial ROS generation by ETC and TCA cycle deplete GSH,
and hence, inactivate the GSH/GPX4 system, and ii) glutamate deficiency due to inhibition of
glutaminolysis in mitochondria inhibits GSH synthesis as a result of low glutamate and cysteine levels.
Thus, this project will explore a novel paradigm by investigating the role of mitochondria in cardiac IRI
ferroptosis. Our central hypothesis is that mitochondria are engaged in ferroptosis induced by cardiac IRI
through diminishing GPX4 activity and inability to control the accumulation of pro-ferroptotic PEox species.
Also, we propose that major cell death mechanisms have different impacts during post-MI/IRI depending
on the severity and duration of post-MI/IRI. Hence, we will evaluate specific biomarkers to distinguish the
contributions of apoptosis, ferroptosis, necroptosis, and pyroptosis to post-MI/IRI. Two approaches will be
employed to mitigate cardiac IRI via i) specific suppression of mtROS production/GSH depletion, and ii)
replenishment of the GSH pool by a potent reductant lipoic/dihydrolipoic acid (LA/DHLA). Specific Aims of
the project will (i) determine comparative contributions of ferroptosis to cardiac dysfunction during IRI, (ii)
explore molecular mechanisms of mitochondria-mediated ferroptotic signaling in cardiac cells, and (iii)
examine the effectiveness of novel inhibitors of ferroptosis against cardiac IRI. The project will establish
the contribution of ferroptosis, in comparison with other major cell de...

## Key facts

- **NIH application ID:** 10409003
- **Project number:** 1R16GM145390-01
- **Recipient organization:** UNIVERSITY OF PUERTO RICO MED SCIENCES
- **Principal Investigator:** Sabzali Javadov
- **Activity code:** R16 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $150,000
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409003

## Citation

> US National Institutes of Health, RePORTER application 10409003, Mitochondria-mediated mechanisms of ferroptosis in response to cardiac ischemia-reperfusion injury (1R16GM145390-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10409003. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*