# Changes in Coenzyme A Levels are a Key Mechanism Regulating Metabolic Pathways

> **NIH NIH R35** · WEST VIRGINIA UNIVERSITY · 2021 · $391,560

## Abstract

Project Summary
Coenzyme A (CoA) is an essential cofactor and the major acyl group carrier in mammalian cells. CoA plays a
central and regulatory role in energy metabolism, as its acyl-CoA derivatives are substrates for hundreds of
metabolic reactions and the posttranslational modification of histones and key metabolic enzymes. CoA-
dependent processes occur in multiple subcellular compartments, and major pools of CoA are found in the
mitochondria, peroxisomes and cytosol. At the whole tissue level, the concentration of CoA is tightly regulated
and dynamically adjusted to changes in the metabolic state. The importance of such a tight control over CoA
levels is underscored by the fact that genetic manipulations that force the concentration of CoA outside of its
homeostatic range result in loss of metabolic regulation and organ function. For example, the inability to increase
CoA levels during a fast blunts fatty acid oxidation and gluconeogenesis in the liver, causing fasting
hypoglycemia. On the other hand, an abnormally high concentration of CoA in skeletal muscle is associated with
decreased muscle mass, ATP levels and exercise performance, highlighting the importance of mechanisms that
prevent the accumulation of this cofactor to toxic levels. The concentration of CoA is regulated by balancing its
synthesis and degradation. The process of CoA degradation is poorly characterized. Furthermore, the
mechanisms that regulate the different subcellular CoA pools are incompletely understood. During the previous
funding cycle, we have characterized the biochemical and regulatory properties of two CoA-degrading enzymes,
Nudt7 and Nudt19, which reside in liver and kidney peroxisomes, respectively. Our published and unpublished
observations support the conclusion that these enzymes regulate peroxisomal lipid metabolism. Furthermore,
deletion of Nudt19 leads to the accumulation of 3-hydroxy-3-methylglutaryl-CoA in the kidneys, suggesting a
connection to cholesterol synthesis. We also identified the first mammalian CoA-degrading enzyme, Nudt8,
which resides in the mitochondria, and we have recently generated Nudt8-/- mice. The existence of CoA-
degrading enzymes in both peroxisomes and mitochondria suggests that these enzymes contribute to the
regulation of the CoA pools within these organelles. The long-term goal of our research program is to understand
the mechanisms that regulate tissue CoA levels and to harness them to manipulate the metabolic network for
the treatment or prevention of metabolic disorders. To move toward this goal, we propose to 1) determine the
mechanisms through which Nudt19 regulates kidney lipid metabolism and kidney function and 2) determine the
role played by Nudt8 in the regulation of the mitochondrial CoA pool and mitochondrial metabolism. This research
program will advance our understanding of the mechanisms that regulate the peroxisomal and mitochondrial
CoA pools. Furthermore, identifying the processes regulated by each CoA-d...

## Key facts

- **NIH application ID:** 10170599
- **Project number:** 2R35GM119528-06
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Roberta Leonardi
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $391,560
- **Award type:** 2
- **Project period:** 2016-07-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170599

## Citation

> US National Institutes of Health, RePORTER application 10170599, Changes in Coenzyme A Levels are a Key Mechanism Regulating Metabolic Pathways (2R35GM119528-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10170599. Licensed CC0.

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