# The effect of mitochondrial CoA degradation on glucose and fatty acid metabolism

> **NIH NIH F31** · WEST VIRGINIA UNIVERSITY · 2020 · $39,190

## Abstract

PROJECT SUMMARY/ABSTRACT
 Mitochondrial metabolism is dependent on coenzyme A (CoA) to support metabolic processes like fatty acid
oxidation, ketogenesis, and gluconeogenesis. Accumulation of CoA results in increased fatty acid oxidation,
which drives gluconeogenesis in diabetes. Abnormally high CoA levels in skeletal muscle blunt mitochondrial
ATP synthesis by decreasing the activity of complex I of the electron transport chain. Despite this evidence
linking increased CoA to metabolic dysregulation, the mechanisms regulating CoA levels within the mitochondria
are currently unknown. Nudt8 is an uncharacterized member of the Nudix hydrolase superfamily. This protein
has been annotated as a potential CoA-degrading enzyme due to its high sequence homology to Nudt7, a
previously characterized CoA diphosphohydrolase that resides in the peroxisomes. Our preliminary data show
that Nudt8 specifically degrades free CoA and CoA thioesters. Additionally, Nudt8 localizes to the mitochondria
and is expressed in highly oxidative tissues such as the heart, kidney, liver, brown adipose tissue, and muscle.
The CoA-degrading activity of Nudt8, coupled with its localization to the mitochondria, suggests a role for this
enzyme in the regulation of mitochondrial CoA levels and thus, metabolism. The proposed research will utilize
adeno-associated virus to achieve over-expression of Nudt8 in the liver, followed by analysis of its effects on
mitochondrial CoA pool size and composition, and on the mitochondrial metabolism of fatty acids and glucose.
Additionally, mechanisms regulating Nudt8 expression and activity will be elucidated.
 The proposed research will be completed with the support of the excellent research facilities available to the
applicant and in collaboration with other investigators within and outside the Department of Biochemistry at West
Virginia University. The highly collaborative environment, combined with a personalized training plan, will allow
the applicant to acquire skills in a broad range of techniques and to develop critical thinking skills, both of which
are essential for a trainee to develop into a successful scientist. The applicant will participate in rigorous course
work and oral presentations; these practices will provide an extensive knowledge base in metabolism and
enhance the ability of the applicant to communicate his scientific ideas. Overall, the proposed combination of
research and training plans will produce a well-rounded scientist as well as valuable insight into the regulation
of the mitochondrial CoA pool and potential of targeting Nudt8 to correct the dysregulated mitochondrial
metabolism that underlies a variety of metabolic diseases.

## Key facts

- **NIH application ID:** 9891848
- **Project number:** 5F31DK118878-02
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Evan W Kerr
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,190
- **Award type:** 5
- **Project period:** 2019-03-17 → 2020-12-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891848

## Citation

> US National Institutes of Health, RePORTER application 9891848, The effect of mitochondrial CoA degradation on glucose and fatty acid metabolism (5F31DK118878-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891848. Licensed CC0.

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