# Regulation of Fuel Utilization by Lysine Acetylation in the Failing Heart

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $481,347

## Abstract

Abstract
Heart failure affects six million people in the United States, and is listed as a causative factor in more than 10%
of deaths. The development of heart failure is linked to several risk factors (including coronary artery disease,
obesity and diabetes), which are increasingly prevalent in Western societies due to diet and other lifestyle
choices. While clinical outcomes have improved over the last three decades, there remain gaps in our
knowledge surrounding the cellular mechanisms that regulate cardiac function. One such gap, and the
scientific focus of this application, is the regulation of fuel substrate utilization by mitochondria in the heart.
Mitochondria provide 95% of the energy required by healthy hearts to maintain contractility, and defects in
mitochondrial bioenergetic activity lead to cardiac energy starvation and heart failure. Mitochondria in the heart
normally provide this energy through the oxidation of fatty acids; however, during heart failure cardiomyocytes
switch to other fuels like glucose. While changes in cardiac substrate preference in heart failure have been well
characterized, we do not fully understand the cellular mechanisms that regulate this process. Our data, and the
current literature, show that mitochondrial function is regulated by lysine acetylation, a post-translational
modification that uses fuel-derived acetyl-CoA as a substrate. We recently identified GCN5L1 as the first
component of the mitochondrial acetyltransferase machinery, and showed that GCN5L1-mediated acetylation
controls mitochondrial bioenergetics in vitro. The objective of this proposal is to understand how GCN5L1
acetylation impacts mitochondrial bioenergetics in the heart, and to investigate how dysregulated energy
substrate utilization can lead to mitochondrial dysfunction, cardiac energy depletion and heart failure. We will
achieve this objective by addressing the following questions: (1) How does GCN5L1 control fatty acid oxidation
in healthy hearts? (2) How does GCN5L1 control substrate utilization during heart failure progression? (3) How
does GCN5L1 regulate cardiac mitochondrial degradation? To answer these questions, we will use a series of
in vivo murine heart failure models and in vitro cell culture studies, combined with metabolic, proteomic and
biochemical techniques, to examine the biology of GCN5L1. We expect that this series of experiments will
provide important new insights on mitochondrial energy substrate regulation, and will highlight GCN5L1 as a
crucial component in the control of metabolic fuel choice, bioenergetics and mitochondrial turnover in the heart.

## Key facts

- **NIH application ID:** 9982397
- **Project number:** 5R01HL132917-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Iain Scott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $481,347
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982397

## Citation

> US National Institutes of Health, RePORTER application 9982397, Regulation of Fuel Utilization by Lysine Acetylation in the Failing Heart (5R01HL132917-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9982397. Licensed CC0.

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