# The Role of GCN5L1 Mediated Mitochondria to Nucleus Retrograde Cardiac Metabolism Reprogramming in Exercise and Heart Failure

> **NIH NIH K08** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $160,488

## Abstract

PROJECT ABSTRACT
 Heart failure is a major public health challenge. Impaired cardiac metabolism is one of the
fundamental mechanisms underlying heart failure progression. Expression profiling of cardiac tissues
reveals repressed transcription factor network activation in heart failure, including Peroxisome
proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), the master regulator of
mitochondrial biogenesis and oxidative phosphorylation, resulting in many metabolic genes
downregulation. In contrast to heart failure, endurance exercise enhances cardiac energetics through the
upregulation of the PGC-1α expression, placing this molecule at the center of the exercise-induced
adaptive response. The molecular mechanisms governing the expression of PGC-1α in response to
exercise or pathological stress leading to heart failure are poorly understood. Mitochondrial function is
also regulated by post-translational modifications of mitochondrial proteins. Our group identified General
Control of Amino-Acid Synthesis 5-like 1 (GCN5L1) as the first acetyltransferase protein responsible for
dynamic mitochondrial acetylation regulating fatty acid oxidation. The role of GCN5L1 in cardiac
energetics regulation and heart failure are largely unknown. In our new preliminary data, we found that
GCN5L1 expression was decreased in human and murine failing hearts and cardiac GCN5L1 knockout
mice (cGCN5L1 KO) displayed exacerbated heart failure progression following transaortic constriction
(TAC), highlighting that GCN5L1 plays an important role in heart failure. Beyond nuclear-mitochondria
one-way communication, emerging evidence show that mitochondria can also engage in retrograde
signaling to the nucleus via metabolic intermediates, reactive oxidative species or peptides to reprogram
metabolic gene transcription. GCN5L1 is predominantly located in mitochondria and is absent in the
nucleus. In our preliminary data, the exercise induced PGC-1α upregulation was blunted in cGCN5L1
KO mice relative to WT controls, and PGC-1α expression was also decreased in TAC cGCN5L1 KO mice
hearts compared to TAC WT mice. These findings suggest that GCN5L1 plays an important role in
controlling PGC-1α expression. In this proposal, leveraging our novel genetic mouse model, we will
test the hypothesis that GCN5L1 plays a critical role in enhancing cardiac bioenergetics through
retrograde activation of PGC-1α signaling during exercise or heart failure development. Three
specific aims are proposed: 1) To test the hypothesis that GCN5L1 induces PGC-1α expression in
response to pressure overload through retrograde activation of p38 MAPK, 2) To test the hypothesis that
GCN5L1 induces PGC-1α expression in response to pressure overload through retrograde histone
acetylation at H3K27, 3) To test the hypothesis that GCN5L1 governs adaptive response to endurance
exercise through retrograde activation of PGC-1α signaling.

## Key facts

- **NIH application ID:** 10372167
- **Project number:** 5K08HL157616-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Manling Zhang
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $160,488
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372167

## Citation

> US National Institutes of Health, RePORTER application 10372167, The Role of GCN5L1 Mediated Mitochondria to Nucleus Retrograde Cardiac Metabolism Reprogramming in Exercise and Heart Failure (5K08HL157616-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10372167. Licensed CC0.

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