# Oxidization of Cardiolipin and its Role in Mitochondrial Dynamics in Pediatric Dilated Cardiomyopathy

> **NIH NIH R56** · UNIVERSITY OF COLORADO DENVER · 2020 · $708,181

## Abstract

Proposal Summary
Treatments for pediatric heart failure (HF) have not improved outcomes significantly over the last 30 years
using evidence-based therapies derived from adult trials. Our previous work and that of others suggests that
age-based mechanistic differences in HF physiology underlie this failure to effectively treat pediatric HF due to
dilated cardiomyopathy (DCM). We show here that mitochondrial energy production is disrupted in pediatric
DCM, with total tissue ATP and phosphocreatine being depleted. DMC hearts have lower mitochondrial copy
number and depleted content of the critical mitochondrial phospholipid, cardiolipin (CL), with associated
derangement of mitochondrial respiratory capacity and metabolism. Quantitative assessment of CL has shown
that there is no alteration in the relative content of the cardiac-specific form of CL, which has four linoleic acid
side-chains (L4CL). Additionally we see evidence that mitochondrial biogenesis and mitophagy are both
upregulated in pediatric DCM. These observations suggest that there is upregulated mitochondrial turnover in
the pediatric DCM, with preservation of L4CL-rich mitochondria, but with lower total tissue mitochondrial
content and disrupted respiration. Preliminary experiments presented in this grant show that oxidized-CL
species are significantly higher in pediatric but not in adult DCM, and additionally that peroxidized CLs
(peroxCL) are very elevated in anthracycline-induced cardiomyopathy which is known to be in part caused by
mitochondrial oxidative stress. Other investigations have correlated oxCL and peroxCL, and translocation of
CL from the inner to the outer mitochondrial membrane with apoptosis and mitophagy. Based on these
observations and our preliminary data, we hypothesize that oxCL and peroxCL are critical signals for
recruitment of mitophagy machinery in the failing cardiomyocyte. We additionally expect to see age-related
differences in response to oxidative stress with younger age conferring increased susceptibility to oxidation of
CL species. Our central hypothesis is that increased oxCL and peroxCL are critical for mitochondrial signaling
in the setting of mitochondrial oxidative stress. We expect that oxCL and peroxCL are important mediators of
mitophagy and apoptotic cell death. In addition, we hypothesize that there are age-dependent mechanisms
that explain differences in mitochondrial response to oxidative stress between pediatric and adult DCM. The
focus of this work is to validate this hypothesis by a translational approach using tissue from DCM patients to
assess mitochondrial response to oxCL/peroxCL, and utilizing a rat ventricular myocyte culture model of
oxidative stress using doxorubicin (Dox) to elucidate the mechanisms CL oxidative events as a function of age
and age-related CL profiles. Finally we propose to use dietary intervention in Dox-treated juvenile rats to show
that oxidation of myocardial CL is dependent on content of specific CL species ...

## Key facts

- **NIH application ID:** 10241784
- **Project number:** 1R56HL153740-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Kathryn C. Chatfield
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $708,181
- **Award type:** 1
- **Project period:** 2020-09-17 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241784

## Citation

> US National Institutes of Health, RePORTER application 10241784, Oxidization of Cardiolipin and its Role in Mitochondrial Dynamics in Pediatric Dilated Cardiomyopathy (1R56HL153740-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241784. Licensed CC0.

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