# Molecular modulation of the mitochondrial Na+/Ca2+ exchanger as a novel therapeutic target for heart failure.

> **NIH NIH F32** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $68,562

## Abstract

PROJECT SUMMARY/ABSTRACT
Heart failure (HF) is a leading cause of disability and death among Americans that currently affects 6 million
people at an economic burden of ~$30 billion per year in the United States alone. The flow of calcium (Ca2+)
into and out of the mitochondria is a key mechanism regulating cellular energy metabolism and cell death.
Since both energetics and cardiomyocyte survival are compromised in the failing heart, altered mitochondrial
Ca2+ (mCa2+) handling has been proposed as a contributing factor in HF. However, the specific changes that
occur in mCa2+ exchange during the development and progression of HF, and the mechanisms that mediate
these effects, remain poorly defined. Therefore, a necessary step before the development of HF therapies
aimed at modulating mCa2+ exchange is to determine exactly how mCa2+ handling changes throughout the
failure process and to understand the specific consequences of chronically-altered mCa2+ exchange on the
function of the failing heart. Recent studies reveal that the mitochondrial sodium-calcium exchanger (NCLX),
which mediates extrusion of mCa2+, is transcriptionally upregulated in human HF. NCLX structure and function
are also controlled via mechanisms including phosphorylation and alternative splicing, and preliminary data
indicate that cardiomyocytes regulate NCLX through these processes during physiological or pathological
stress. Initial findings also suggest that transgenic overexpression of NCLX to enhance cardiomyocyte mCa2+
extrusion is sufficient to protect contractile function and attenuate pathological remodeling in mouse models of
non-ischemic HF. Based on these data, we hypothesize that cardiomyocytes increase net NCLX activity as an
adaptive mechanism to control mCa2+ homeostasis in HF. Here we will pursue Specific Aims employing genetic
mouse models with net gain or reduction of cardiac NCLX function to examine the contribution of altered NCLX
activity to the development and progression of chronic HF and assess the therapeutic potential of NCLX
modulation for this disease. We will also combine robust proteomic and molecular approaches with direct in
vitro assessments of NCLX function to determine the endogenous mechanisms that control NCLX activity
within the heart. This project will be the first to causatively examine how alterations in NCLX activity protect or
predispose the heart to failure when subjected to sustained pathological stress, and will generate fundamental
knowledge that can be exploited for therapeutic control of NCLX activity. These findings will have broad
translational relevance not only for cardiac disease, but also for other conditions characterized by altered mCa2+
homeostasis such as Alzheimer’s disease and neurodegeneration. A detailed training plan outlining the
mentorship to be provided to the Applicant and the resources and technical support available at Temple
University’s Center for Translational Medicine has been developed to ensure successf...

## Key facts

- **NIH application ID:** 10128197
- **Project number:** 5F32HL151146-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Joanne Frances Garbincius
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $68,562
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128197

## Citation

> US National Institutes of Health, RePORTER application 10128197, Molecular modulation of the mitochondrial Na+/Ca2+ exchanger as a novel therapeutic target for heart failure. (5F32HL151146-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10128197. Licensed CC0.

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