# Ferroptosis in the Heart: Iron Calcium Crosstalk and Compartmentalization

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2022 · $603,528

## Abstract

Summary
Approximately one person dies from heart disease every 30 seconds in the United States. About 1.5 million
Americans die from myocardial infarction each year. Clinically, genetic disorders (e.g. hereditary
hemochromatosis) and repeated blood transfusions (as required for sickle cell anemia and beta thalassemia)
are known to cause Fe accumulation in the heart with iron overload cardiomyopathy being a major cause of
death. It has been recently reported that dilated cardiomyopathy occurs in up to 95% of patients with
Duchenne muscular dystrophy and that iron levels are elevated in mouse models. Furthermore, iron levels are
known to be elevated in the heart after ischemia followed by reperfusion. Nevertheless, the underlying
mechanism(s) involved in Fe associated cardiotoxicity remain unclear. Calcium and iron are both known to
play vital cellular roles in the heart. Cells exhibit a remarkable dependence on keen regulation of calcium and
iron concentrations. Cellular dysregulation of either ion can result in systolic and diastolic dysfunction and
ultimately cardiomyopathy. Loss or disruption of normal homeostasis of cellular calcium and/or cellular iron
concentrations can not only cause direct myocardial cardiotoxicity, but can also result in loss of myocardial
excitability and abnormal excitation contraction coupling. We propose that a cross talk between calcium and
iron combined results in a highly cardiotoxic cellular environment. We posit that the presence of iron can result
in cell death via an underappreciated pathway, i.e. ferroptosis in the heart resulting in cardiomyopathy as well
as ischemia reperfusion injury. Furthermore, we propose a similar link between myocardial stunning seen after
brief periods of ischemia reperfusion to be in part due to the same cross talk resulting in a partially reversible
reduction in myocardial systolic function. Linking the transport of calcium and iron signaling is the mitochondria
Ca uniporter (mCU) and the activation of transient receptor potential canonical channels. We show that iron
can regulate TRPC ion channel function. Our preliminary data have shown that TRPC channels are directly
activated by iron. Importantly, activation of TRPCs has been implicated in calcium paradox injury and post-
myocardial infarction remodeling. We aim to demonstrate that neither calcium nor iron are simply passive
participants in cellular processes, but when forces are joined result in systolic and diastolic failure of the heart,
cardiotoxcity, and together are predictive of a reduced lifespan in humans. We will demonstrate that it is
cellular diastolic calcium and mitochondrial calcium that defines cell death and myocardial function with iron
loading. We hypothesize that mCU accounts for mitochondrial iron overload and that an interaction (or
crosstalk) between elevated diastolic calcium and increased mitochondrial iron results in a highly volatile and
cardiotoxic environment that causes cardiac cell death via ferrop...

## Key facts

- **NIH application ID:** 10364032
- **Project number:** 1R01HL157116-01A1
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Judith K Gwathmey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $603,528
- **Award type:** 1
- **Project period:** 2021-12-25 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364032

## Citation

> US National Institutes of Health, RePORTER application 10364032, Ferroptosis in the Heart: Iron Calcium Crosstalk and Compartmentalization (1R01HL157116-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10364032. Licensed CC0.

---

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