Sunday, November 24, 2024
11/24/2024
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 Our published and unpublished observations support the conclusion that these enzymes regulate peroxisomal lipid metabolism.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-degrading enzyme will aid in the development of strategies to target and correct specific CoA-dependent pathways in metabolic disorders.
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