# The role of energy sensor signaling in mitochondrial cardiomyopathy

> **NIH NIH K08** · UNIVERSITY OF IOWA · 2020 · $160,628

## Abstract

ABSTRACT TEXT: Approximately 5.7 million adult Americans have heart failure and this prevalence is
projected to increase 25% by 2030. Despite improvement in heart failure treatment, including device therapy
and cardiac transplantation, the mortality rate remains high. Cardiac arrhythmia is among the most common
cause of mortality in heart failure patients. We and others have demonstrated the roles of mitochondrial
dysfunction in heart failure due to various etiologies. Among these, mitochondrial cardiomyopathy
demonstrates the most severe impairment of mitochondrial function. Mitochondrial disease is a group of rare
genetic disorder due to mutation of mitochondrial proteins, most encoded by nuclear DNA and a few by
mitochondrial DNA. Although only approximately 40% of patients with mitochondrial disease exhibit cardiac
involvement, the presence of cardiomyopathy significantly predicts poor outcome and to date there is no
effective therapy. Novel therapeutics is urgently needed to treat such patients. This study proposes
manipulation of energy sensor signaling to enhance mitochondrial function, in order to treat mitochondrial
disease, focusing on mitochondrial cardiomyopathy. Our preliminary data and previous publications suggest
that energy sensor signaling, including AMP-activated protein kinase (AMPK) and nicotinamide adenine
dinucleotide (NAD+), play an important role to maintain mitochondrial function in mitochondrial disease as well
as during development of heart failure. This study proposes strategies of manipulating energy sensor signaling
(AMPK, NAD+, sirtuin) to improve mitochondrial function and to rescue cardiac arrhythmia in a mouse model of
complex I deficiency with mitochondrial cardiomyopathy (Aim 1). To better recapitulate human disease, I
propose to model human mitochondrial cardiomyopathy on a dish, using human induced pluripotent cell
derived cardiomyocytes with mitochondrial complex I deficiency (Aim 2) and use the same strategies to rescue
arrhythmia and cardiomyocyte dysfunction. The training award provides an excellent opportunity to learn novel
technology of iPS, gene editing (such as CRISPR/cas), measurement of biomechanics and electrophysiology
of cardiomyocytes as functional parameter of “disease in a dish”, and extend my training in mitochondrial
biology. This proposal is significant because it advances our scientific understanding of the relationship of
mitochondrial dysfunction and heart failure and arrhythmia and test the method to rescue mitochondrial
disease. Completion of this study may lead to development of novel therapy for untreatable mitochondrial
disease. Finally, since mitochondrial dysfunction is evident in various etiologies of end-stage heart failure, the
mitochondrial protective strategies proposed in this study may also be beneficial in other types of heart
diseases.

## Key facts

- **NIH application ID:** 9857657
- **Project number:** 5K08HL145138-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Dao-Fu Dai
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $160,628
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857657

## Citation

> US National Institutes of Health, RePORTER application 9857657, The role of energy sensor signaling in mitochondrial cardiomyopathy (5K08HL145138-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857657. Licensed CC0.

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