# Mechanistic insights into the role of mitochondrial iron in doxorubicin-induced cardiomyopathy using human induced pluripotent stem cells

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $396,250

## Abstract

The clinical use of doxorubicin (DOX, and anticancer drug) is limited due to its cardiotoxic side effects. The
mechanism of DOX-induced cardiotoxicity (DIC) is not totally understood. We recently showed that DOX causes
mitochondrial (as opposed to total cellular) iron accumulation, and that a reduction in mitochondrial iron leads to
protection against DIC. However, these studies were predominantly performed in vitro and in animal models,
and it is not clear whether higher mitochondrial iron contributes to DIC susceptibility in patients. To extend these
findings beyond animal models, we have established several lines of human induced pluripotent stem cell-
derived cardiomyocytes (hiPSC-CM) from patients who either experienced DIC (DIC-CM) or did not have
cardiotoxicity (noDIC-CM) after exposure to DOX, and showed that they recapitulate the patients’ phenotype in
vitro, and that they are susceptible to a special form of iron-mediated cell death called “ferroptosis”. Using RNA-
seq, we have also identified a number of mitochondrial iron genes to be altered in DIC samples after DOX
treatment. Finally, we have demonstrated that hiPSC-CM from DIC patients display elevated mitochondrial iron
after DOX exposure. Our central hypothesis is that mitochondrial iron plays a key role in the susceptibility
to DIC in humans, and that a reduction in mitochondrial iron (either by iron chelators or by modulation
of genes involved in mitochondrial iron homeostasis) alter cardiomyocyte susceptibility to DOX. We also
hypothesize that DOX clearance from subcellular compartments is regulated by mitochondrial iron
through mitophagy, and that this process is impaired in DIC. In Aim 1, we will determine whether DIC-CM
are more susceptible to DOX toxicity due to mitochondrial iron accumulation, and that a reduction in
mitochondrial iron improves cell viability in these cells. We will modulate mitochondrial iron in DIC-CM and
noDIC-CM using mitochondrial permeable iron chelators (including new chelators identified in our lab), followed
by exposure to DOX and assessment of ferroptosis and cell viability. In Aim 2, we will determine whether
modulation of mitochondrial iron-related genes identified in our RNA-seq analysis alters susceptibility to DOX.
Our studies demonstrated that mRNA levels of ABCB7 and ABCB8 (proteins that mediate mitochondrial iron
export) and MFRN2 (a mitochondrial iron importer) are altered with DOX treatment. We will delete ABCB7 or
ABCB8 in hiPSC from noDIC (which would result in an increase in mitochondrial iron) and MFRN2 in hiPSC from
DIC (resulting in a reduction in mitochondrial iron) using CRISPR-Cas9, followed by generation of hiPSC-CM,
exposure to DOX, and assessment of cell viability. Finally, in Aim 3, we will determine whether mitochondrial
iron regulates DOX clearance and that inherent defects in DOX clearance promotes susceptibility to DIC. We
will assess DOX clearance, mitochondrial dynamics and mitophagy in noDIC-CM and DIC-CM after DOX a...

## Key facts

- **NIH application ID:** 10120719
- **Project number:** 5R01HL140927-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Hossein Ardehali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2020-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120719

## Citation

> US National Institutes of Health, RePORTER application 10120719, Mechanistic insights into the role of mitochondrial iron in doxorubicin-induced cardiomyopathy using human induced pluripotent stem cells (5R01HL140927-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10120719. Licensed CC0.

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