# Probing the Role of Mitochondrial Short-chain Carbon Homeostasis in the Hypertrophied and Failing Heart

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $743,357

## Abstract

SUMMARY
Current therapies for heart failure (HF) are largely directed at maladaptive extra-cardiac neurohormonal circuits
in a “one size fits all” approach. There is a significant unmet need for mechanism-based therapies directly
targeting the heart during early stages of HF. Increasing evidence has shown that during the development of
heart failure, mitochondrial generation of ATP becomes dysregulated. A well-established metabolic signature of
the failing heart is a shift from using fatty acids as the chief fuel source of the normal heart, to other fuels such
as glucose. This fuel shift occurs early in the development of cardiac hypertrophy and failure. However, the
potential linkage of this cardiac fuel switch to the progressive diminution in mitochondrial respiratory function and
ATP producing capacity during the development of HF has not been established beyond a mere association.
During the current funding period, we have made a series of discoveries that support the premise that
disturbances in cardiac fatty acid oxidation (FAO) contribute to mitochondrial energetic dysfunction and the
development of HF including: 1) identification of distinct “bottlenecks” in the terminal steps of the FAO pathway
setting the stage for depletion of key cofactors such as Coenzyme A (CoA) and diversion of reducing equivalents
away from complex I of the electron transport chain; 2) the ketone body, 3-hydroxybutryate (3OHB), an efficient
cardiac fuel that bypasses long-chain FAO, reduces cardiac remodeling and ventricular dysfunction in small and
large animal models of HF; and 3) increasing cardiac mitochondrial oxidative capacity, including FAO flux, by
cardiac-specific deletion of the gene encoding RIP140 (Nrip1) prevents cardiac hypertrophic growth and reduces
cardiac remodeling and dysfunction caused by pressure overload in mice. These findings have led to the central
hypotheses of this multi-PI R01 renewal proposal: Downregulation of FAO in the hypertrophied heart results
in bottlenecking within the -oxidation spiral leading to reduced capacity for mitochondrial ATP
production and; reduced FAO flux sets the stage for utilization of carbon sources from glucose and
other sources in anabolic pathways necessary for cardiac hypertrophic growth. These hypotheses will be
tested by two aims. In Aim 1, we will conduct in-depth assessment of the cardiac functional, mitochondrial,
proteomic and genomic response of wild-type, csRIP140-/- (high FAO), and csPPAR-/- (low FAO) mice during
development of HF in mice. Aim 2 is designed to determine the mechanisms whereby RIP140 deficiency defends
against pathological cardiac hypertrophic growth. The long-term objectives of the proposed work are to define
the mechanistic events leading to mitochondrial energetic collapse in the failing heart and to identify nodal
regulatory points that could serve as candidate therapeutic strategies aimed at re-balancing fuel utilization and
enhancing mitochondrial ATP-producing capacity ai...

## Key facts

- **NIH application ID:** 10296253
- **Project number:** 2R01HL128349-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DANIEL PATRICK KELLY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $743,357
- **Award type:** 2
- **Project period:** 2016-04-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296253

## Citation

> US National Institutes of Health, RePORTER application 10296253, Probing the Role of Mitochondrial Short-chain Carbon Homeostasis in the Hypertrophied and Failing Heart (2R01HL128349-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10296253. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*