# Mechanisms of lipid-induced bioenergetic stress in muscle

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $589,999

## Abstract

Abstract
Our work in the area of mitochondrial function, energy homeostasis and metabolomics has led us
to discover a remarkably strong association between adverse cardiometabolic outcomes and
tissue/blood levels of acylcarnitine (AC) conjugates. These metabolites derive from acyl-CoA
intermediates of fuel catabolism and permit mitochondrial export of excess carbons. For the past
decade, our laboratory has remained keenly committed to answering a crucial question: What is
this AC signature telling us about the interplay between mitochondria and metabolic
disease? The current proposal aims to test the hypothesis that AC accumulation reflects a
bottleneck in the fatty acid oxidation (FAO) pathway that diminishes mitochondrial power and
efficiency. This prediction stems from unique insights gained via the application of a new
mitochondrial diagnostics platform developed by our laboratory during the previous grant cycle.
In simple terms, our assays serve as an in vitro “stress test” that evaluates how well a given
population of mitochondria, fueled by specific mixtures of carbon substrates, responds to a graded
energetic challenge. We have been combining this platform with mass spectrometry-based
metabolomics, proteomics and 13C metabolic flux analysis to evaluate mitochondrial remodeling
and corresponding changes in respiratory power and efficiency in response to a variety of
nutritional and genetic maneuvers. New and exciting findings suggest that AC accumulation
reflects a critical thermodynamic vulnerability in the mitochondrial FAO pathway, and thereby serves
as a signal of bioenergetic stress, en route to compromised bioenergetics and impending
tissue/organ failure. Moreover, our preliminary studies suggest mitochondria resident in untrained
skeletal muscles and failing hearts are especially vulnerable to this lipid-induced “traffic jam”; and
that ketones are uniquely able to circumvent the roadblock to defend cellular energetics in settings
of metabolic stress. Accordingly, we also aim to test the hypothesis that ketone oxidation plays
an essential role in permitting the salutary mitochondrial and metabolic adaptations known to
occur in response to regimens of intermittent fasting.

## Key facts

- **NIH application ID:** 9937824
- **Project number:** 5R01DK089312-10
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** DEBORAH M MUOIO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $589,999
- **Award type:** 5
- **Project period:** 2010-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937824

## Citation

> US National Institutes of Health, RePORTER application 9937824, Mechanisms of lipid-induced bioenergetic stress in muscle (5R01DK089312-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9937824. Licensed CC0.

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