Role of Acetylation in Metabolic Regulation

The fundamental characteristic of life is metabolism. When metabolism is disrupted, it can lead to many diseases, and when metabolism ceases, life will come to an end. Therefore, metabolism is closely related to health and longevity. In fact, about 80% of human diseases are metabolic diseases. If metabolism could be regulated, could many diseases be controlled? How is metabolism actually regulated?

In 2010, the journal "Science" published two groundbreaking articles simultaneously, revealing the acetylation regulation mechanism of metabolic enzymes and opening up a new field of research in metabolic regulation. The research found that acetylation modification of metabolic enzymes is extremely widespread, including the tricarboxylic acid cycle, gluconeogenesis, glycolysis, glycogen metabolism, fatty acid metabolism, urea cycle, and others. Surprisingly, up to 90% of the enzymes involved in these metabolic pathways undergo acetylation modification. Moreover, acetylation-mediated metabolic regulation is widely present from prokaryotes to eukaryotes, indicating that acetylation-mediated metabolic regulation is highly conserved in evolution.

Research focusing on acetylation from a metabolic perspective is called mechanistic exploration. On the other hand, research focusing on metabolism from the perspective of acetylation is referred to as phenotype validation.

Metabolism and Acetylation Relationship

Metabolism and acetylation are closely intertwined, and their relationship can be broadly categorized into two levels.

Regulation of Acetylation by Metabolism

At the first level, metabolism regulates acetylation. During acetylation, the acetyl group donor, acetyl coenzyme A (acetyl-CoA), a common metabolite, is regulated by nutrient availability. Increased nutrient abundance upregulates cellular levels of acetyl-CoA, consequently enhancing acetyltransferase activity, leading to acetylation of substrate proteins. Conversely, in deacetylation, the metabolite nicotinamide adenine dinucleotide (NAD^+) is also subject to nutritional regulation. Nutrient deficiency increases its concentration, promoting the activity of deacetylase enzymes such as sirtuins, leading to substrate protein deacetylation.

Metabolism Regulation by Acetylation

At the second level, metabolism is regulated by acetylation through direct and indirect pathways. Direct regulation involves modulating metabolic enzyme activity, where acetylation modifies metabolic enzymes, altering their catalytic activity and thus directly controlling downstream metabolites. Indirect regulation involves modulating the expression of metabolism-related genes. Acetylation of histones and transcription factors, for instance, can affect the expression of metabolism-related genes, thereby exerting indirect control over metabolism.

Metabolic Diseases and Metabolic Health

In metabolic diseases, loss of acetylation sites on metabolic enzymes disrupts the regulation of enzyme activity and stability by acetylation modifications, leading to metabolic disorders and disease onset. Many metabolic diseases, including metabolic syndrome (obesity, diabetes, heart failure), and cancers, are associated with aberrant acetylation. For instance, abnormal acetylation levels of the gluconeogenic enzyme PEPCK1 are linked to diabetes development. Knocking out specific acetyltransferase genes for PEPCK1 results in decreased acetylation levels, leading to glucose abnormalities and potentially diabetes. In obesity, the loss of function of the deacetylase Sirtuin3 is associated with obesity development, as Sirtuin3 activates key enzymes in lipid metabolism. Studies show that mice with Sirtuin3 deficiency fed a high-fat diet are more prone to obesity compared to wild-type mice. Additionally, cancer, characterized by elevated glucose uptake and unrestricted glycolysis, exhibits abnormal acetylation or deacetylation of many metabolic enzymes in various cancer types, promoting tumor growth through increased lipid synthesis, glycolysis, or lactate production.

Furthermore, as metabolic health is closely linked to longevity, research on acetylation modifications in metabolic health has shown considerable promise. Factors such as calorie restriction, high physical activity, and circadian rhythm feeding patterns demonstrate distinct metabolic profiles and differential acetylation levels. Notably, a study published in Cell Metabolism in 2015, aimed at investigating exercise metabolism, conducted proteomic, phosphoproteomic, and acetylomic experiments, revealing that acetylation modifications are most closely associated with metabolism.

Mitochondrial Protein Acetylation Is Dynamic with Exercise (Katherine A et al., 2015)

Metabolism and Plant Stress

In recent years, acetylation modifications in plants have gained attention, although research in plants lags significantly behind that in higher animals, especially regarding non-histone acetylation studies. Recent analyses of acetylation components in model plants have revealed a close relationship between acetylation and metabolism. Moreover, in the field of abiotic and biotic stress, studies on acetylation metabolism have shown tremendous potential. Genomic data indicate significant differences in acetylation modifications on crucial metabolic pathways under stress conditions. Thus, research in this area holds immense promise.

Conclusion

Acetylation is a widespread regulatory mechanism found in various cellular compartments such as the nucleus, cytoplasm, and mitochondria, participating in gene expression, metabolism, and other life processes. Acetylation of metabolic enzymes greatly enhances an organism's adaptability to its environment. Therefore, research in both animal and plant systems holds the potential for significant value.

References

1. Overmyer, Katherine A., et al. "Maximal oxidative capacity during exercise is associated with skeletal muscle fuel selection and dynamic changes in mitochondrial protein acetylation." Cell metabolism 21.3 (2015): 468-478.
2. Rhoads, Timothy W., et al. "Caloric restriction engages hepatic RNA processing mechanisms in rhesus monkeys." Cell metabolism 27.3 (2018): 677-688.