# Determining the Biological Effects of Mitochondrial Acyl Toxicity

> **NIH NIH R01** · EAST CAROLINA UNIVERSITY · 2020 · $463,883

## Abstract

PROJECT SUMMARY
During acute metabolic stress and chronic metabolic disease, such as obesity and diabetes, the accumulation
of fatty acid oxidation intermediary metabolites has long been suspected of toxicity. Among these possible
lipotoxic metabolites are long-chain acylcarnitines (LCACs), which purportedly interfere with critical physiological
processes including insulin signaling, calcium homeostasis, and mitochondrial function. However,
mechanistically linking defects in these processes to LCAC accumulation has been difficult due to a lack of
LCAC-accumulating pre-clinical models. We overcame this barrier by developing a unique mouse model of
LCAC accumulation by deleting the enzyme that catabolizes LCACs, carnitine palmitoyltransferase-2 specifically
in skeletal muscle (Cpt2Sk-/-). Consistent with the suspected roles of LCACs effects on biology, our preliminary
data demonstrate that Cpt2Sk-/- muscles have reduced force production and mitochondrial dysfunction. Our
preliminary data also demonstrate large accumulation of LCACs within oxidative muscle fibers, thus are the most
vulnerable to potential LCAC toxicity. While our Cpt2Sk-/- model provides consistently elevated LCACs, the
physiological outcomes are confounded by energy deprivation due to mitochondrial FAO deficiency. To mitigate
concerns surrounding this confounding variable, we will employ three complimentary mouse models of muscle-
specific FAO deficiency: 1) Cpt2Sk-/- that accumulate LCACs across the cell; 2) carnitine acylcarnitine translocase
(CactSk-/-) mice that accumulate LCACs outside of the mitochondria; and 3) acyl-CoA synthetase 1 (Acsl1Sk-/-)
mice that do not accumulate LCACs at all. Here, we will use this three-model system to determine the role of
LCACs on insulin signaling, calcium homeostasis, and mitochondrial function. Results will be the first to provide
requisite experimental contrast to unveil direct versus indirect effects of LCACs on cell physiology.

## Key facts

- **NIH application ID:** 10034718
- **Project number:** 1R01DK125812-01
- **Recipient organization:** EAST CAROLINA UNIVERSITY
- **Principal Investigator:** Jessica M Ellis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,883
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10034718

## Citation

> US National Institutes of Health, RePORTER application 10034718, Determining the Biological Effects of Mitochondrial Acyl Toxicity (1R01DK125812-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10034718. Licensed CC0.

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