# Investigating the novel role of acetylation in cardiac mitochondrial bioenergetics and function in the aging heart

> **NIH NIH K99** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $173,017

## Abstract

Cardiac mitochondrial dysfunction is central to the pathogenesis of aging and many age related diseases.
Mitochondria supply the bioenergetic capacity for cardiac contractile function through oxidation of fuel
substrates and a complete control of this system is indispensable to maintain cardiac efficiency. Specifically,
the role of Hydroxyacyl-CoA Dehydrogenase (HADHA) and Long Chain Acyl-CoA Dehydrogenase (LCAD) in
catalyzing the oxidation of long chain fatty acids in the heart is well studied and their dysfunction is associated
with decreased fatty acid oxidation (FAO) and cardiac energy depletion. However, studies focused on
understanding the cellular mechanisms that regulate these key mitochondrial energy substrate enzymes in the
aging heart are scarce. In a recent study, we described that increased acetylation increases the activities of
LCAD and HADHA in diet induced obesity, which was mediated by changes in the expression of mitochondrial
acetyltransferase GCN5L1 and deacetylase SIRT3. In the aging heart, we observe increased GCN5L1 and
decreased SIRT3 expression resulting in an increased acetylation status of HADHA and LCAD. Based on
these observations, we hypothesize that GCN5L1 and SIRT3 control HADHA and LCAD acetylation, and that
dysregulation of this mechanism in aging contributes to reduced mitochondrial bioenergetics and
cardiomyocyte energy depletion. To test our central hypothesis, we propose the following aims: 1. We will
investigate how acetylation regulates the activity of HADHA and LCAD in young, middle aged and old mouse
hearts. Using high resolution mass spectrometry based proteomics; we will identify acetylation sites, relative
quantification and assess their impact in key biological processes and enzymatic functions. 2. We will
investigate the mechanisms associated with regulation of HADHA and LCAD activity in young, middle aged
and old mouse hearts. We will use novel GCN5L1 and SIRT3 cardiac KO animal to delineate the molecular
mechanisms underlying changes in HADHA and LCAD acetylation in aging process. 3. We will investigate how
changes in fatty acid oxidation protein acetylation impacts mitochondrial bioenergetics and cardiac contractile
function in aging heart. The long term goal of this study is to understand the regulatory role of cardiac
mitochondrial acetylation in human aging and age related diseases. Our results will improve our understanding
of acetylation mediated regulation of FAO enzymes in aging mitochondrial biology and provide novel insights
on regulation of fuel substrate usage in the aging heart and their contribution towards improving mitochondrial
and cardiac function with age.

## Key facts

- **NIH application ID:** 10083227
- **Project number:** 5K99HL146905-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Dharendra Thapa
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $173,017
- **Award type:** 5
- **Project period:** 2020-01-08 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083227

## Citation

> US National Institutes of Health, RePORTER application 10083227, Investigating the novel role of acetylation in cardiac mitochondrial bioenergetics and function in the aging heart (5K99HL146905-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10083227. Licensed CC0.

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